Evidence-Based Reviews

Deciding if a patient’s depressive episodes are “atypical” can be difficult because key pieces of the diagnostic puzzle are missing. Notwithstanding DSM-IV criteria, atypical depression’s definition remains unclear. This creates a therapeutic dilemma because we know that patients with atypical depression respond differently to antidepressants:

• Monoamine oxidase inhibitors (MAOIs) may be most effective, but their side effects can be troublesome.
• Tricyclics are clearly less effective than MAOIs, but the newer antidepressants’ role in treating atypical depressive symptoms has not been adequately explored.

We offer recommendations for diagnosing and treating atypical depression and address issues that may affect your clinical approach. These include possible overemphasis on mood reactivity in DSM-IV, shortcomings in studies defining the atypical depressive syndrome, and the potential role of biological markers in clarifying this challenging diagnosis.

Features of atypical depression

Atypical depression, as defined in DSM-IV,¹ is characterized by mood reactivity and two or more of the following criteria:

• hypersomnia
• increased appetite or weight gain
• leaden paralysis (heavy, leaden feeling in arms or legs)
• longstanding sensitivity to interpersonal rejection that results in significant social or occupational impairment (Table 1 ).

An estimated 16 to 23% of patients with unipolar depression present with atypical features.² These rates are higher among patients with bipolar disorder.^2,3

Distinctive features. Studies comparing atypical depression with typical or melancholic depression suggest that atypical depression may be distinct in epidemiology, family history, comorbidity, and course of illness (Table 2). Specifically, atypical depression has a higher female-to-male ratio and earlier age of onset.⁴ Patients with atypical depression have higher rates of comorbid panic disorder,^4,5 social phobia,^4,5 bipolar II disorder,⁵ and bulimia⁶ than do those with typical depression.

Family members of patients with atypical depression are more likely to have atypical features during a depressive episode than are family members of patients with melancholic depression.⁷ These findings suggest a genetic component to atypical depression. Atypical depressive episodes also may be more likely to become chronic.^4,8

Not all patients are alike. Studies of the diagnostic stability of atypical depression over time suggest that patients exhibiting atypical features are heterogeneous.⁹ Some longitudinal studies report reasonable diagnostic stability, with 59% to 100% of patients with an index episode of atypical depression exhibiting atypical features 12 to 24 months later.^9,10 In a follow-up study of patients in remission from an episode of atypical depression, 64% of patients suffering a relapse were again found to have atypical features.¹¹

Table 1

MOOD EPISODES: DSM-IV CRITERIA FOR ATYPICAL FEATURES SPECIFIER

The following criteria must be present in the last 2 weeks of the episode
Criterion A.  Mood reactivity (ie, mood brightens in response to positive events)
Criterion B. Two or more of the following:  Increased appetite or weight gain  Hypersomnia  Leaden paralysis  Longstanding sensitivity to interpersonal rejection

Although numerous studies have failed to replicate one or more of these findings,^4,8 several investigators have concluded that atypical depression is a distinct and valid sub-type of major depression.^4,7,8

Antidepressant dilemmas

Unlike typical or melancholic depression, atypical depression responds more robustly to MAOIs than to tricyclic antidepressants (TCAs).¹² MAOIs are roughly twice as effective as TCAs (response rate 72% vs. 44%, respectively), according to a meta-analysis of six studies comparing MAOIs and TCAs in patients with atypical depression.¹³

Clinicians rarely use MAOIs as first-line antidepressants, however, because of side effects and potential dietary and drug interactions. A depressed patient is thus unlikely to receive MAOIs unless the clinician strongly suspects that the presentation is atypical.

SSRIs. Few studies have evaluated how patients with atypical depression respond to newer antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). This lack of evidence creates a dilemma when treating atypical depression, as SSRIs are widely used in depressed patients, including those with atypical features.

One study found fluoxetine and phenelzine comparably effective in atypical depression,¹⁴ while another found sertraline works as well as moclobe-mide.¹⁵ However, the fluoxetine study was limited by a relatively small sample size (n=42), and both studies lacked placebo controls.

Some studies have suggested that SSRIs are less effective than MAOIs¹⁶ or as effective as TCAs in depressed patients with atypical features.^17,18 However, one of these trials was limited by a small sample size (n=28),¹⁸ and only one was placebo-controlled.¹⁷

Bupropion. Studies of other antidepressants in atypical depression also are limited. In two separate trials, depressed patients with atypical features showed a greater response to bupropion than did depressed patients with typical features.^19,20

Bupropion—a combined dopaminergic-noradrenergic antidepressant—appears to have stimulating properties that may help patients with hypersomnia and hyperphagia. Like MAOIs, bupropion also appears to have a greater effect on dopaminergic systems than either TCAs or SSRIs.

 

Recommendation. The most prudent approach appears to be using SSRIs or bupropion as first-line treatment for atypical depression and reserving MAOIs for patients who do not respond.

Attempts to define atypical depression

Although atypical depression responds differently to MAOIs than to TCAs, it is unclear which patients will respond preferentially to MAOIs. Early attempts to classify this subgroup recognized that these patients display symptom clusters, including:

• anxious depression (prominent anxiety symptoms)
• anergic depression (prominent fatigue and/or psychomotor retardation)
• and depression with reversed vegetative symptoms (hypersomnia and increased weight/appetite).^7,21

Researchers have focused on patients with different combinations of these symptom profiles when defining the atypical depressive syndrome. Some have defined atypical depression as anxious temperament and reactive mood; others, as depression with reversed vegetative symptoms and severe fatigue; still others employ aspects of both profiles, as does DSM-IV.²¹ As a result of this confusion, investigators have demonstrated the preferential response to MAOIs in groups that exhibit different “atypical” symptoms.

Mood reactivity. The importance of mood reactivity in the diagnosis of atypical depression has been debated. DSM-IV requires mood reactivity for the diagnosis, perhaps to clearly differentiate melancholia from atypical depression.⁷ Yet some studies have demonstrated the preferential MAOI response in patients without this symptom.

Table 2

HOW ATYPICAL DEPRESSION COMPARES WITH MELANCHOLIC OR ‘TYPICAL’ DEPRESSION

Feature	Atypical depression	Melancholic (MEL)/typical (TYP) depression
Symptom
Sleep	Increased	Decreased
Appetite	Increased	Decreased
Age of onset	Late teens to early 20s	Mid to late 30s
Female:male ratio	> 2:1	Between 1:1 and 2:1
Frequency of bipolar II disorder	Increased compared with MEL/TYP
Duration of episodes	Increased compared with MEL/TYP
Biology
HPA axis activity	Low to normal	High
Comorbidity
Panic disorder, social phobia, bulimia	Frequency increased compared with MEL/TYP

The Columbia group, from whose work the DSM-IV definition was adopted, performed several convincing studies showing clear superiority of MAOIs in patients who had reactive mood and displayed at least two additional atypical features, such as reversed vegetative symptoms and anergia.²² Patients with reactive mood and only one additional atypical symptom (classified as “probable” atypical depression) also displayed the preferential response to MAOIs, whereas patients who displayed mood reactivity alone did not.¹²

Thase et al,²³ however, reported that reversed vegetative symptoms were more common with nonreactive mood (48%) than with reactive mood (16%) in patients with highly recurrent depression. Moreover, patients who displayed reversed vegetative symptoms without mood reactivity showed the same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Table 3

HOW ANTIDEPRESSANTS COMPARE IN CLINICAL TRIALS OF ATYPICAL DEPRESSION

MAOIs	8 controlled trials found MAOI > placebo 6 controlled trials found MAOI > TCA
TCAs	6 controlled trials found MAOI > TCA
SSRIs	2 controlled trials found SSRI = MAOI 1 trial found MAOI > SSRI 2 trials found SSRI = TCA
Bupropion	1 open-label trial found bupropion more effective in atypical depression than in typical depression 1 open-label trial found bupropion effective in depression with hypersomnia 1 retrospective study found bupropion > fluoxetine in atypical depression
> more effective than
= as effective as

More evidence suggests that mood reactivity should not be given the hierarchical importance it holds in the DSM-IV definition of atypical depression. In studies using latent class and cluster analyses, mood reactivity did not correlate with any other atypical feature,^4,21 whereas hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity appear to be associated with one another.

Recommendation. Mood reactivity’s uncertain status in atypical depression’s definition makes it difficult to predict which patients may respond preferentially to MAOIs, as many patients present with other atypical features and nonreactive mood. Most recently, it has been suggested that atypical depression’s diagnostic criteria should be modified so that mood reactivity is not required but is one of five atypical features, of which three must be present for the diagnosis.²⁴

Biological markers of depression

Atypical depression’s definition might be clarified if specific depressive symptoms could be linked to any biological markers. One proposed marker is decreased HPA axis activity, possibly caused by a central deficiency of corticotropin-releasing hormone (CRH),²⁵ a potent HPA axis stimulator.

• HPA axis hyperactivity—presumably caused by increased CRH activity in the central nervous system—has been linked to melancholic depressive symptoms—particularly insomnia and reduced appetite.²⁶
• Normal or diminished HPA axis activity—suggested by normal cortisol levels, low levels of CRH in cerebrospinal fluid, and increased frequency of dexamethasone suppression—has been associated with some atypical depressive features—specifically reversed vegetative symptoms.^27-29

However, no studies have examined whether low HPA axis activity is associated with other atypical symptoms listed in DSM-IV. Research is needed to determine whether HPA axis hypoactivity is associated only with reversed vegetative symptoms or with atypical depression per se.

Obesity and eating disorders. Depressed patients who are obese or present with eating disorders may overlap with the atypical subtype and may respond better to some drug interventions than to others. Evidence suggests that depression—particularly the atypical subtype—is associated with increased rates of obesity^8,29 and eating disorders.^8,30

 

In our clinical experience, the combination of venlafaxine and bupropion can be effective for both depression and excessive eating in these patients, many of whom also exhibit other atypical features. A possible explanation is that the combined pharmacologic effect of venlafaxine and bupropion resembles that of the MAOIs (increased synaptic availability of serotonin, norepinephrine, and dopamine) without many MAOI side effects, such as weight gain.

We have, however, also observed treatment-emergent hypomania when using this drug combination, which is consistent with:

• the idea that mood reactivity and rejection sensitivity may be markers for bipolar disorder
• the often-reported high rate of bipolar II disorder among patients with atypical depression.⁵

In obese patients with bipolar II disorder, we have found that adding topiramate to mood stabilizer therapy can help treat both mood instability and overeating.^31,32 same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Related resources

• Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal. Am J Psychiatry 2002;159(9):1470-9.
• Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002;7(3):254-75.
• Nierenberg AA, Alpert JE, Pava J, Rosenbaum JF, Fava M. Course and treatment of atypical depression. J Clin Psychiatry 1998;59(suppl 18):5-9.

Drug brand names

• Bupropion • Wellbutrin
• Fluoxetine • Prozac
• Moclobemide • Manerix
• Phenelzine • Nardil
• Sertraline • Zoloft
• Topiramate • Topamax
• Venlafaxine • Effexor

Disclosure

Dr. Nelson receives grant/research support from Eli Lilly & Co. and Wyeth Pharmaceuticals and is on the speakers bureau of Wyeth Pharmaceuticals.

Dr. McElroy is a consultant or scientific advisor to Abbott Laboratories, Bristol-Myers Squibb Co., Elan Corp., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co., Novartis Pharmaceuticals Corp., Ortho-McNeil Pharmaceutical, UCB Pharma, and Wyeth Pharmaceuticals. She receives research support from Forest Laboratories, GlaxoSmithKline, Elan Corp., Eli Lilly & Co., Merck & Co., Ortho-McNeil Pharmaceutical, Pfizer Inc., Sanofi-Synthelabo, and UCB Pharma.

Deciding if a patient’s depressive episodes are “atypical” can be difficult because key pieces of the diagnostic puzzle are missing. Notwithstanding DSM-IV criteria, atypical depression’s definition remains unclear. This creates a therapeutic dilemma because we know that patients with atypical depression respond differently to antidepressants:

• Monoamine oxidase inhibitors (MAOIs) may be most effective, but their side effects can be troublesome.
• Tricyclics are clearly less effective than MAOIs, but the newer antidepressants’ role in treating atypical depressive symptoms has not been adequately explored.

We offer recommendations for diagnosing and treating atypical depression and address issues that may affect your clinical approach. These include possible overemphasis on mood reactivity in DSM-IV, shortcomings in studies defining the atypical depressive syndrome, and the potential role of biological markers in clarifying this challenging diagnosis.

Features of atypical depression

Atypical depression, as defined in DSM-IV,¹ is characterized by mood reactivity and two or more of the following criteria:

• hypersomnia
• increased appetite or weight gain
• leaden paralysis (heavy, leaden feeling in arms or legs)
• longstanding sensitivity to interpersonal rejection that results in significant social or occupational impairment (Table 1 ).

An estimated 16 to 23% of patients with unipolar depression present with atypical features.² These rates are higher among patients with bipolar disorder.^2,3

Distinctive features. Studies comparing atypical depression with typical or melancholic depression suggest that atypical depression may be distinct in epidemiology, family history, comorbidity, and course of illness (Table 2). Specifically, atypical depression has a higher female-to-male ratio and earlier age of onset.⁴ Patients with atypical depression have higher rates of comorbid panic disorder,^4,5 social phobia,^4,5 bipolar II disorder,⁵ and bulimia⁶ than do those with typical depression.

Family members of patients with atypical depression are more likely to have atypical features during a depressive episode than are family members of patients with melancholic depression.⁷ These findings suggest a genetic component to atypical depression. Atypical depressive episodes also may be more likely to become chronic.^4,8

Not all patients are alike. Studies of the diagnostic stability of atypical depression over time suggest that patients exhibiting atypical features are heterogeneous.⁹ Some longitudinal studies report reasonable diagnostic stability, with 59% to 100% of patients with an index episode of atypical depression exhibiting atypical features 12 to 24 months later.^9,10 In a follow-up study of patients in remission from an episode of atypical depression, 64% of patients suffering a relapse were again found to have atypical features.¹¹

Table 1

MOOD EPISODES: DSM-IV CRITERIA FOR ATYPICAL FEATURES SPECIFIER

The following criteria must be present in the last 2 weeks of the episode
Criterion A.  Mood reactivity (ie, mood brightens in response to positive events)
Criterion B. Two or more of the following:  Increased appetite or weight gain  Hypersomnia  Leaden paralysis  Longstanding sensitivity to interpersonal rejection

Although numerous studies have failed to replicate one or more of these findings,^4,8 several investigators have concluded that atypical depression is a distinct and valid sub-type of major depression.^4,7,8

Antidepressant dilemmas

Unlike typical or melancholic depression, atypical depression responds more robustly to MAOIs than to tricyclic antidepressants (TCAs).¹² MAOIs are roughly twice as effective as TCAs (response rate 72% vs. 44%, respectively), according to a meta-analysis of six studies comparing MAOIs and TCAs in patients with atypical depression.¹³

Clinicians rarely use MAOIs as first-line antidepressants, however, because of side effects and potential dietary and drug interactions. A depressed patient is thus unlikely to receive MAOIs unless the clinician strongly suspects that the presentation is atypical.

SSRIs. Few studies have evaluated how patients with atypical depression respond to newer antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). This lack of evidence creates a dilemma when treating atypical depression, as SSRIs are widely used in depressed patients, including those with atypical features.

One study found fluoxetine and phenelzine comparably effective in atypical depression,¹⁴ while another found sertraline works as well as moclobe-mide.¹⁵ However, the fluoxetine study was limited by a relatively small sample size (n=42), and both studies lacked placebo controls.

Some studies have suggested that SSRIs are less effective than MAOIs¹⁶ or as effective as TCAs in depressed patients with atypical features.^17,18 However, one of these trials was limited by a small sample size (n=28),¹⁸ and only one was placebo-controlled.¹⁷

Bupropion. Studies of other antidepressants in atypical depression also are limited. In two separate trials, depressed patients with atypical features showed a greater response to bupropion than did depressed patients with typical features.^19,20

Bupropion—a combined dopaminergic-noradrenergic antidepressant—appears to have stimulating properties that may help patients with hypersomnia and hyperphagia. Like MAOIs, bupropion also appears to have a greater effect on dopaminergic systems than either TCAs or SSRIs.

 

Recommendation. The most prudent approach appears to be using SSRIs or bupropion as first-line treatment for atypical depression and reserving MAOIs for patients who do not respond.

Attempts to define atypical depression

Although atypical depression responds differently to MAOIs than to TCAs, it is unclear which patients will respond preferentially to MAOIs. Early attempts to classify this subgroup recognized that these patients display symptom clusters, including:

• anxious depression (prominent anxiety symptoms)
• anergic depression (prominent fatigue and/or psychomotor retardation)
• and depression with reversed vegetative symptoms (hypersomnia and increased weight/appetite).^7,21

Researchers have focused on patients with different combinations of these symptom profiles when defining the atypical depressive syndrome. Some have defined atypical depression as anxious temperament and reactive mood; others, as depression with reversed vegetative symptoms and severe fatigue; still others employ aspects of both profiles, as does DSM-IV.²¹ As a result of this confusion, investigators have demonstrated the preferential response to MAOIs in groups that exhibit different “atypical” symptoms.

Mood reactivity. The importance of mood reactivity in the diagnosis of atypical depression has been debated. DSM-IV requires mood reactivity for the diagnosis, perhaps to clearly differentiate melancholia from atypical depression.⁷ Yet some studies have demonstrated the preferential MAOI response in patients without this symptom.

Table 2

HOW ATYPICAL DEPRESSION COMPARES WITH MELANCHOLIC OR ‘TYPICAL’ DEPRESSION

Feature	Atypical depression	Melancholic (MEL)/typical (TYP) depression
Symptom
Sleep	Increased	Decreased
Appetite	Increased	Decreased
Age of onset	Late teens to early 20s	Mid to late 30s
Female:male ratio	> 2:1	Between 1:1 and 2:1
Frequency of bipolar II disorder	Increased compared with MEL/TYP
Duration of episodes	Increased compared with MEL/TYP
Biology
HPA axis activity	Low to normal	High
Comorbidity
Panic disorder, social phobia, bulimia	Frequency increased compared with MEL/TYP

The Columbia group, from whose work the DSM-IV definition was adopted, performed several convincing studies showing clear superiority of MAOIs in patients who had reactive mood and displayed at least two additional atypical features, such as reversed vegetative symptoms and anergia.²² Patients with reactive mood and only one additional atypical symptom (classified as “probable” atypical depression) also displayed the preferential response to MAOIs, whereas patients who displayed mood reactivity alone did not.¹²

Thase et al,²³ however, reported that reversed vegetative symptoms were more common with nonreactive mood (48%) than with reactive mood (16%) in patients with highly recurrent depression. Moreover, patients who displayed reversed vegetative symptoms without mood reactivity showed the same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Table 3

HOW ANTIDEPRESSANTS COMPARE IN CLINICAL TRIALS OF ATYPICAL DEPRESSION

MAOIs	8 controlled trials found MAOI > placebo 6 controlled trials found MAOI > TCA
TCAs	6 controlled trials found MAOI > TCA
SSRIs	2 controlled trials found SSRI = MAOI 1 trial found MAOI > SSRI 2 trials found SSRI = TCA
Bupropion	1 open-label trial found bupropion more effective in atypical depression than in typical depression 1 open-label trial found bupropion effective in depression with hypersomnia 1 retrospective study found bupropion > fluoxetine in atypical depression
> more effective than
= as effective as

More evidence suggests that mood reactivity should not be given the hierarchical importance it holds in the DSM-IV definition of atypical depression. In studies using latent class and cluster analyses, mood reactivity did not correlate with any other atypical feature,^4,21 whereas hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity appear to be associated with one another.

Recommendation. Mood reactivity’s uncertain status in atypical depression’s definition makes it difficult to predict which patients may respond preferentially to MAOIs, as many patients present with other atypical features and nonreactive mood. Most recently, it has been suggested that atypical depression’s diagnostic criteria should be modified so that mood reactivity is not required but is one of five atypical features, of which three must be present for the diagnosis.²⁴

Biological markers of depression

Atypical depression’s definition might be clarified if specific depressive symptoms could be linked to any biological markers. One proposed marker is decreased HPA axis activity, possibly caused by a central deficiency of corticotropin-releasing hormone (CRH),²⁵ a potent HPA axis stimulator.

• HPA axis hyperactivity—presumably caused by increased CRH activity in the central nervous system—has been linked to melancholic depressive symptoms—particularly insomnia and reduced appetite.²⁶
• Normal or diminished HPA axis activity—suggested by normal cortisol levels, low levels of CRH in cerebrospinal fluid, and increased frequency of dexamethasone suppression—has been associated with some atypical depressive features—specifically reversed vegetative symptoms.^27-29

However, no studies have examined whether low HPA axis activity is associated with other atypical symptoms listed in DSM-IV. Research is needed to determine whether HPA axis hypoactivity is associated only with reversed vegetative symptoms or with atypical depression per se.

Obesity and eating disorders. Depressed patients who are obese or present with eating disorders may overlap with the atypical subtype and may respond better to some drug interventions than to others. Evidence suggests that depression—particularly the atypical subtype—is associated with increased rates of obesity^8,29 and eating disorders.^8,30

 

In our clinical experience, the combination of venlafaxine and bupropion can be effective for both depression and excessive eating in these patients, many of whom also exhibit other atypical features. A possible explanation is that the combined pharmacologic effect of venlafaxine and bupropion resembles that of the MAOIs (increased synaptic availability of serotonin, norepinephrine, and dopamine) without many MAOI side effects, such as weight gain.

We have, however, also observed treatment-emergent hypomania when using this drug combination, which is consistent with:

• the idea that mood reactivity and rejection sensitivity may be markers for bipolar disorder
• the often-reported high rate of bipolar II disorder among patients with atypical depression.⁵

In obese patients with bipolar II disorder, we have found that adding topiramate to mood stabilizer therapy can help treat both mood instability and overeating.^31,32 same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Related resources

• Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal. Am J Psychiatry 2002;159(9):1470-9.
• Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002;7(3):254-75.
• Nierenberg AA, Alpert JE, Pava J, Rosenbaum JF, Fava M. Course and treatment of atypical depression. J Clin Psychiatry 1998;59(suppl 18):5-9.

Drug brand names

• Bupropion • Wellbutrin
• Fluoxetine • Prozac
• Moclobemide • Manerix
• Phenelzine • Nardil
• Sertraline • Zoloft
• Topiramate • Topamax
• Venlafaxine • Effexor

Disclosure

Dr. Nelson receives grant/research support from Eli Lilly & Co. and Wyeth Pharmaceuticals and is on the speakers bureau of Wyeth Pharmaceuticals.

Dr. McElroy is a consultant or scientific advisor to Abbott Laboratories, Bristol-Myers Squibb Co., Elan Corp., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co., Novartis Pharmaceuticals Corp., Ortho-McNeil Pharmaceutical, UCB Pharma, and Wyeth Pharmaceuticals. She receives research support from Forest Laboratories, GlaxoSmithKline, Elan Corp., Eli Lilly & Co., Merck & Co., Ortho-McNeil Pharmaceutical, Pfizer Inc., Sanofi-Synthelabo, and UCB Pharma.

Deciding if a patient’s depressive episodes are “atypical” can be difficult because key pieces of the diagnostic puzzle are missing. Notwithstanding DSM-IV criteria, atypical depression’s definition remains unclear. This creates a therapeutic dilemma because we know that patients with atypical depression respond differently to antidepressants:

• Monoamine oxidase inhibitors (MAOIs) may be most effective, but their side effects can be troublesome.
• Tricyclics are clearly less effective than MAOIs, but the newer antidepressants’ role in treating atypical depressive symptoms has not been adequately explored.

We offer recommendations for diagnosing and treating atypical depression and address issues that may affect your clinical approach. These include possible overemphasis on mood reactivity in DSM-IV, shortcomings in studies defining the atypical depressive syndrome, and the potential role of biological markers in clarifying this challenging diagnosis.

Features of atypical depression

Atypical depression, as defined in DSM-IV,¹ is characterized by mood reactivity and two or more of the following criteria:

• hypersomnia
• increased appetite or weight gain
• leaden paralysis (heavy, leaden feeling in arms or legs)
• longstanding sensitivity to interpersonal rejection that results in significant social or occupational impairment (Table 1 ).

An estimated 16 to 23% of patients with unipolar depression present with atypical features.² These rates are higher among patients with bipolar disorder.^2,3

Distinctive features. Studies comparing atypical depression with typical or melancholic depression suggest that atypical depression may be distinct in epidemiology, family history, comorbidity, and course of illness (Table 2). Specifically, atypical depression has a higher female-to-male ratio and earlier age of onset.⁴ Patients with atypical depression have higher rates of comorbid panic disorder,^4,5 social phobia,^4,5 bipolar II disorder,⁵ and bulimia⁶ than do those with typical depression.

Family members of patients with atypical depression are more likely to have atypical features during a depressive episode than are family members of patients with melancholic depression.⁷ These findings suggest a genetic component to atypical depression. Atypical depressive episodes also may be more likely to become chronic.^4,8

Not all patients are alike. Studies of the diagnostic stability of atypical depression over time suggest that patients exhibiting atypical features are heterogeneous.⁹ Some longitudinal studies report reasonable diagnostic stability, with 59% to 100% of patients with an index episode of atypical depression exhibiting atypical features 12 to 24 months later.^9,10 In a follow-up study of patients in remission from an episode of atypical depression, 64% of patients suffering a relapse were again found to have atypical features.¹¹

Table 1

MOOD EPISODES: DSM-IV CRITERIA FOR ATYPICAL FEATURES SPECIFIER

The following criteria must be present in the last 2 weeks of the episode
Criterion A.  Mood reactivity (ie, mood brightens in response to positive events)
Criterion B. Two or more of the following:  Increased appetite or weight gain  Hypersomnia  Leaden paralysis  Longstanding sensitivity to interpersonal rejection

Although numerous studies have failed to replicate one or more of these findings,^4,8 several investigators have concluded that atypical depression is a distinct and valid sub-type of major depression.^4,7,8

Antidepressant dilemmas

Unlike typical or melancholic depression, atypical depression responds more robustly to MAOIs than to tricyclic antidepressants (TCAs).¹² MAOIs are roughly twice as effective as TCAs (response rate 72% vs. 44%, respectively), according to a meta-analysis of six studies comparing MAOIs and TCAs in patients with atypical depression.¹³

Clinicians rarely use MAOIs as first-line antidepressants, however, because of side effects and potential dietary and drug interactions. A depressed patient is thus unlikely to receive MAOIs unless the clinician strongly suspects that the presentation is atypical.

SSRIs. Few studies have evaluated how patients with atypical depression respond to newer antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). This lack of evidence creates a dilemma when treating atypical depression, as SSRIs are widely used in depressed patients, including those with atypical features.

One study found fluoxetine and phenelzine comparably effective in atypical depression,¹⁴ while another found sertraline works as well as moclobe-mide.¹⁵ However, the fluoxetine study was limited by a relatively small sample size (n=42), and both studies lacked placebo controls.

Some studies have suggested that SSRIs are less effective than MAOIs¹⁶ or as effective as TCAs in depressed patients with atypical features.^17,18 However, one of these trials was limited by a small sample size (n=28),¹⁸ and only one was placebo-controlled.¹⁷

Bupropion. Studies of other antidepressants in atypical depression also are limited. In two separate trials, depressed patients with atypical features showed a greater response to bupropion than did depressed patients with typical features.^19,20

Bupropion—a combined dopaminergic-noradrenergic antidepressant—appears to have stimulating properties that may help patients with hypersomnia and hyperphagia. Like MAOIs, bupropion also appears to have a greater effect on dopaminergic systems than either TCAs or SSRIs.

 

Recommendation. The most prudent approach appears to be using SSRIs or bupropion as first-line treatment for atypical depression and reserving MAOIs for patients who do not respond.

Attempts to define atypical depression

Although atypical depression responds differently to MAOIs than to TCAs, it is unclear which patients will respond preferentially to MAOIs. Early attempts to classify this subgroup recognized that these patients display symptom clusters, including:

• anxious depression (prominent anxiety symptoms)
• anergic depression (prominent fatigue and/or psychomotor retardation)
• and depression with reversed vegetative symptoms (hypersomnia and increased weight/appetite).^7,21

Researchers have focused on patients with different combinations of these symptom profiles when defining the atypical depressive syndrome. Some have defined atypical depression as anxious temperament and reactive mood; others, as depression with reversed vegetative symptoms and severe fatigue; still others employ aspects of both profiles, as does DSM-IV.²¹ As a result of this confusion, investigators have demonstrated the preferential response to MAOIs in groups that exhibit different “atypical” symptoms.

Mood reactivity. The importance of mood reactivity in the diagnosis of atypical depression has been debated. DSM-IV requires mood reactivity for the diagnosis, perhaps to clearly differentiate melancholia from atypical depression.⁷ Yet some studies have demonstrated the preferential MAOI response in patients without this symptom.

Table 2

HOW ATYPICAL DEPRESSION COMPARES WITH MELANCHOLIC OR ‘TYPICAL’ DEPRESSION

Feature	Atypical depression	Melancholic (MEL)/typical (TYP) depression
Symptom
Sleep	Increased	Decreased
Appetite	Increased	Decreased
Age of onset	Late teens to early 20s	Mid to late 30s
Female:male ratio	> 2:1	Between 1:1 and 2:1
Frequency of bipolar II disorder	Increased compared with MEL/TYP
Duration of episodes	Increased compared with MEL/TYP
Biology
HPA axis activity	Low to normal	High
Comorbidity
Panic disorder, social phobia, bulimia	Frequency increased compared with MEL/TYP

The Columbia group, from whose work the DSM-IV definition was adopted, performed several convincing studies showing clear superiority of MAOIs in patients who had reactive mood and displayed at least two additional atypical features, such as reversed vegetative symptoms and anergia.²² Patients with reactive mood and only one additional atypical symptom (classified as “probable” atypical depression) also displayed the preferential response to MAOIs, whereas patients who displayed mood reactivity alone did not.¹²

Thase et al,²³ however, reported that reversed vegetative symptoms were more common with nonreactive mood (48%) than with reactive mood (16%) in patients with highly recurrent depression. Moreover, patients who displayed reversed vegetative symptoms without mood reactivity showed the same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Table 3

HOW ANTIDEPRESSANTS COMPARE IN CLINICAL TRIALS OF ATYPICAL DEPRESSION

MAOIs	8 controlled trials found MAOI > placebo 6 controlled trials found MAOI > TCA
TCAs	6 controlled trials found MAOI > TCA
SSRIs	2 controlled trials found SSRI = MAOI 1 trial found MAOI > SSRI 2 trials found SSRI = TCA
Bupropion	1 open-label trial found bupropion more effective in atypical depression than in typical depression 1 open-label trial found bupropion effective in depression with hypersomnia 1 retrospective study found bupropion > fluoxetine in atypical depression
> more effective than
= as effective as

More evidence suggests that mood reactivity should not be given the hierarchical importance it holds in the DSM-IV definition of atypical depression. In studies using latent class and cluster analyses, mood reactivity did not correlate with any other atypical feature,^4,21 whereas hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity appear to be associated with one another.

Recommendation. Mood reactivity’s uncertain status in atypical depression’s definition makes it difficult to predict which patients may respond preferentially to MAOIs, as many patients present with other atypical features and nonreactive mood. Most recently, it has been suggested that atypical depression’s diagnostic criteria should be modified so that mood reactivity is not required but is one of five atypical features, of which three must be present for the diagnosis.²⁴

Biological markers of depression

Atypical depression’s definition might be clarified if specific depressive symptoms could be linked to any biological markers. One proposed marker is decreased HPA axis activity, possibly caused by a central deficiency of corticotropin-releasing hormone (CRH),²⁵ a potent HPA axis stimulator.

• HPA axis hyperactivity—presumably caused by increased CRH activity in the central nervous system—has been linked to melancholic depressive symptoms—particularly insomnia and reduced appetite.²⁶
• Normal or diminished HPA axis activity—suggested by normal cortisol levels, low levels of CRH in cerebrospinal fluid, and increased frequency of dexamethasone suppression—has been associated with some atypical depressive features—specifically reversed vegetative symptoms.^27-29

However, no studies have examined whether low HPA axis activity is associated with other atypical symptoms listed in DSM-IV. Research is needed to determine whether HPA axis hypoactivity is associated only with reversed vegetative symptoms or with atypical depression per se.

Obesity and eating disorders. Depressed patients who are obese or present with eating disorders may overlap with the atypical subtype and may respond better to some drug interventions than to others. Evidence suggests that depression—particularly the atypical subtype—is associated with increased rates of obesity^8,29 and eating disorders.^8,30

 

In our clinical experience, the combination of venlafaxine and bupropion can be effective for both depression and excessive eating in these patients, many of whom also exhibit other atypical features. A possible explanation is that the combined pharmacologic effect of venlafaxine and bupropion resembles that of the MAOIs (increased synaptic availability of serotonin, norepinephrine, and dopamine) without many MAOI side effects, such as weight gain.

We have, however, also observed treatment-emergent hypomania when using this drug combination, which is consistent with:

• the idea that mood reactivity and rejection sensitivity may be markers for bipolar disorder
• the often-reported high rate of bipolar II disorder among patients with atypical depression.⁵

In obese patients with bipolar II disorder, we have found that adding topiramate to mood stabilizer therapy can help treat both mood instability and overeating.^31,32 same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Related resources

• Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal. Am J Psychiatry 2002;159(9):1470-9.
• Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002;7(3):254-75.
• Nierenberg AA, Alpert JE, Pava J, Rosenbaum JF, Fava M. Course and treatment of atypical depression. J Clin Psychiatry 1998;59(suppl 18):5-9.

Drug brand names

• Bupropion • Wellbutrin
• Fluoxetine • Prozac
• Moclobemide • Manerix
• Phenelzine • Nardil
• Sertraline • Zoloft
• Topiramate • Topamax
• Venlafaxine • Effexor

Disclosure

Dr. Nelson receives grant/research support from Eli Lilly & Co. and Wyeth Pharmaceuticals and is on the speakers bureau of Wyeth Pharmaceuticals.

Dr. McElroy is a consultant or scientific advisor to Abbott Laboratories, Bristol-Myers Squibb Co., Elan Corp., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co., Novartis Pharmaceuticals Corp., Ortho-McNeil Pharmaceutical, UCB Pharma, and Wyeth Pharmaceuticals. She receives research support from Forest Laboratories, GlaxoSmithKline, Elan Corp., Eli Lilly & Co., Merck & Co., Ortho-McNeil Pharmaceutical, Pfizer Inc., Sanofi-Synthelabo, and UCB Pharma.

Aggression, irritability, repetitive phenomena, or hyperactivity can interfere with the education and treatment of patients with autism.¹ To assist clinicians in selecting drug therapies to control these behaviors, we developed a medication strategy based on controlled studies and our experience in an autism specialty clinic. In this article, we:

• offer an overview with two algorithms that show how to target maladaptive behaviors in patients of all ages with autism
• and discuss the controlled clinical evidence behind this approach.

Targeting behaviors

A multimodal approach is used to manage autistic disorder. Although behavioral techniques are useful and may decrease the need for drug therapy, one or more medications are often required to target severe maladaptive behaviors. Although we recommend that you consider all interfering behaviors when selecting medications, it is important to:

• initially focus on symptoms—such as self-injurious behaviors and aggression—that acutely affect the patient’s and caregiver’s safety
• consider the patient as being pre- or postpubertal, as developmental level may affect medication response.

Figure 1 BEHAVIOR-BASED DRUG THERAPY FOR CHILDREN WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc. Aggression or self-injury. When drug therapy is needed to control severe aggression or self-injurious behavior, we recommend a trial of an atypical antipsychotic for prepubertal patients (Figure 1). Alternately, you may consider a mood stabilizer such as lithium or divalproex for an adult patient with prominent symptoms (Figure 2). However, mood stabilizer use requires monitoring by venipuncture for potential blood cell or liver function abnormalities.

Atypical antipsychotics are associated with adverse effects including sedation, weight gain, extrapyramidal symptoms, tardive dyskinesia, and hyperprolactinemia. Therefore, you may need to monitor weight, lipid profile, glucose, liver function, and cardiac function when using this class of agent.

Repetitive phenomena can be addressed with selective serotonin reuptake inhibitors (SSRIs), although SSRIs may be activating in children and tend to be better tolerated in older adolescents and adults.

Anxiety. In children with anxiety, we suggest a trial of mirtazapine—because of its calming properties—before you try an SSRI. If both the SSRI and mirtazapine are ineffective, try an α2-adrenergic agonist. A baseline ECG is recommended before starting an α2-adrenergic agonist—particularly clonidine, which has been associated with rare cardiovascular events. Overall, these agents are well tolerated.

Hyperactivity, inattention. Anecdotal evidence indicates that stimulants may worsen symptoms of aggression, hyperactivity, and irritability in individuals with autism. Therefore, we suggest you start with an α2-adrenergic agonist when target symptoms include hyperactivity and inattention. Consider a stimulant trial if the α2-adrenergic agonist does not control the symptoms.

An atypical antipsychotic is generally recommended for autistic individuals with treatment-resistant hyperactivity and inattention, anxiety, and interfering repetitive behaviors.

Drug therapy. As summarized below, controlled evidence for behavior-based drug therapy of autism (Table.) suggests a role for antipsychotics, antidepressants, mood stabilizers, and psychostimulants in managing interfering behaviors.

Antipsychotics

Risperidone. Two controlled studies have reported the effect of risperidone on autism’s related symptoms.

McDougle et al conducted a 12-week, double-blind, placebo-controlled trial of risperidone, mean 2.9 mg/d, in adults with pervasive developmental disorders.² Repetitive behavior, aggression, anxiety, irritability, depression, and general behavioral symptoms decreased in 8 of 14 patients, as measured by Clinical Global Impressions (CGI) scale ratings of “much improved” or “very much improved.” Sixteen subjects who received placebo showed no response. Transient sedation was the most common adverse effect.

More recently, the National Institutes of Mental Health-sponsored Research Units on Pediatric Psychopharmacology (RUPP) Autism Network completed a double-blind, placebo-controlled study of risperidone, 0.5 to 3.5 mg/d (mean 1.8 mg/d), in 101 children and adolescents with autism.³ After 8 weeks, 69% of the risperidone group responded, compared with 12% of the placebo group. Response was defined as:

• at least a 25% decrease in the Irritability subscale score of the Aberrant Behavior Checklist (ABC)
• and CGI ratings of “much improved” or “very much improved.”

Risperidone was effective for treating aggression, agitation, hyperactivity, and repetitive behavior. Adverse effects included weight gain (mean 2.7 kg vs. 0.8 kg with placebo), increased appetite, sedation, dizziness, and hypersalivation.

Olanzapine. A 12-week, open-label study of olanzapine, mean 7.8 mg/d, was conducted in eight patients ages 5 to 42 diagnosed with a pervasive developmental disorder.⁴ Hyperactivity, social relatedness, self-injurious behavior, aggression, anxiety, and depression improved significantly in six of seven patients who completed the trial, as measured by a CGI classification of “much improved” or “very much improved.” Adverse effects included weight gain (mean 18.4 lbs) in six patients and sedation in three.

 

Malone et al conducted a 6-week, open-label comparison of olanzapine, mean 7.9 mg/d, versus haloperidol, mean 1.4 mg/d, in 12 children with autistic disorder.⁵ Five of six subjects who received olanzapine responded, compared with three of six who received haloperidol, as determined by a CGI classification of “much improved” or “very much improved.” Anger/uncooperativeness and hyperactivity were reduced significantly only in the olanzapine group. Weight gain and sedation were the most common adverse effects with both medications. Weight gain was greater with olanzapine (mean 9 lbs) than with haloperidol (mean 3.2 lbs).

Quetiapine. Only one report addresses quetiapine in children and adolescents with autism.⁶ Two of six patients completed this 16-week, open-label trial of quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/d). The group showed no statistically significant improvement in behavioral symptoms. Two patients achieved CGI ratings of “much improved” or “very much improved.” One subject dropped out after a possible seizure during treatment, and three others withdrew because of sedation or lack of response.

Ziprasidone. McDougle et al conducted a naturalistic, open-label study of ziprasidone, 20 to 120 mg/d (mean 59.2 mg/d), in 12 subjects ages 8 to 20. Nine were diagnosed with autism and three with a pervasive developmental disorder not otherwise specified (NOS). Six subjects responded across 14 weeks of treatment, as determined by ratings of “much improved” or “very much improved” on the CGI.⁷

Transient sedation was the most common adverse effect. Mean weight change was −5.83 lbs (range −35 to +6 lbs). Despite ziprasidone’s reported risk of causing abnormal cardiac rhythms, no cardiovascular adverse effects were reported.

Clozapine. Three case reports but no controlled studies have addressed clozapine in autistic disorder:

• Zuddas et al used clozapine, 100 to 200 mg/d for 3 months, to treat three children ages 8 to 12.⁸ Previous trials of haloperidol were ineffective, but the patients’ aggression, hyperactivity, negativism, and language and communication skills improved with clozapine, as measured by the Children’s Psychiatric Rating Scale (CPRS) and the Self-Injurious Behavior Questionnaire.
• Chen et al used clozapine, 275 mg/d, to treat a 17-year-old male inpatient.⁹ Aggression was significantly reduced across 15 days, as determined by a 21-question modified version of the CPRS. Side effects included mild constipation and excessive salivation.
• Clozapine, 300 mg/d for 2 months, reduced aggression in an adult patient and was associated with progressive and marked improvement of aggression and social interaction, as measured by the CGI and the Visual Analog Scale (VAS). No agranulocytosis or extrapyramidal symptoms were observed across 5 years of therapy.¹⁰

Clozapine’s adverse effect profile probably explains why the literature contains so little data regarding its use in patients with autism. This drug’s propensity to lower the seizure threshold discourages its use in a population predisposed to seizures. Autistic patients also have a low tolerance for frequent venipuncture and limited ability to communicate agranulocytosis symptoms.

Antidepressants

Clomipramine—a tricyclic antidepressant with anti-obsessional properties—has shown some positive effects in treating autistic behaviors. Even so, this compound is prescribed infrequently to patients with autism because of low tolerability. In one recent double-blind, placebo-controlled, crossover study, 36 autistic patients ages 10 to 36 received:

• clomipramine, 100 to 150 mg/d (mean 128 mg/d)
• haloperidol, 1 to 1.5 mg/d (mean 1.3 mg/d)

or placebo for 7 weeks. Among patients who completed the trial, clomipramine and haloperidol were similarly effective in reducing overall autistic symptoms, irritability, and stereotypy. However, only 37.5% of those receiving clomipramine completed the study because of adverse effects, behavioral problems, and general lack of efficacy.¹¹

Table

CONTROLLED EVIDENCE* FOR BEHAVIOR-BASED DRUG THERAPY OF AUTISM

Medication	Behaviors improved	Significant adverse effects	Comments
Risperidone 2	Aggression, irritability	Mild transient sedation	Conducted in adults
Risperidone 3	Aggression, irritability	Weight gain, increased appetite, sedation, tremor, hypersalivation	Largest controlled study to date in children with autism
Clomipramine 11	Irritability, stereotypy	Tachycardia, tremors, diaphoresis, insomnia, nausea	Conducted in children and adults
Fluvoxamine 12	Aggression, repetitive phenomena	Nausea, sedation	No published controlled pediatric data; unpublished pediatric data unfavorable
Clonidine 24	Hyperactivity, irritability, stereotypies, oppositional behavior, aggression, self-injury	Hypotension, sedation, decreased activity	Small number of subjects
Clonidine 25	Impulsivity, self-stimulation, hyperarousal	Sedation and fatigue	Small number of subjects
Methylphenidate 28	Hyperactivity, irritability	Social withdrawal and irritability	Adverse effects more common at 0.6 mg/kg/dose
• Double-blind, placebo-controlled studies

Fluvoxamine. Only one double-blind, placebo-controlled study has examined the use of an SSRI in autistic disorder.¹² In this 12-week trial, 30 adults with autism received fluvoxamine, mean 276.7 mg/d, or placebo. Eight of 15 subjects in the fluvoxamine group were categorized as “much improved” or “very much improved” on the CGI.

Fluvoxamine was much more effective than placebo in reducing repetitive thoughts and behavior, aggression, and maladaptive behavior. Adverse effects included minimal sedation and nausea.

Unpublished data of McDougle et al suggest that autistic children and adolescents respond less favorably than adults to fluvoxamine. In a 12-week, double-blind, placebocontrolled trial in patients ages 5 to 18, only 1 of 18 subjects responded to fluvoxamine at a mean dosage of 106.9 mg/d. Agitation, increased aggression, hyperactivity, and increased repetitive behavior were reported.

 

Fluoxetine. Seven autistic patients ages 9 to 20 were treated with fluoxetine, 20 to 80 mg/d (mean 37.1 mg/d) in an 18-month longitudinal open trial. Irritability, lethargy, and stereotypy improved, as measured by the ABC.¹³ Adverse effects included increased hyperactivity and transient appetite suppression.

In another open-label trial of 37 autistic children ages 2 to 7, response was rated by investigators as “excellent” in 11 and “good” in another 11 who received fluoxetine, 0.2 to 1.4 mg/kg/d. However, aggression was a frequent cause for drug discontinuation during the 21-month study.¹⁴

Sertraline. In an open-label trial, Steingard et al treated nine autistic children ages 6 to 12 with sertraline, 25 to 50 mg/d for 2 to 8 weeks. Clinical improvement was observed in irritability, transition-associated anxiety, and need for sameness in eight of the children.¹⁵

Figure 2 BEHAVIOR-BASED DRUG THERAPY FOR POSTPUBERTAL PATIENTS WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc.In an open-label trial, 42 adults with pervasive developmental disorders were treated for 12 weeks with sertraline, 50 to 200 mg/d (mean 122 mg/d). Twenty-four (57%) achieved CGI ratings of “much improved” or “very much improved” in aggressive and repetitive behavior.¹⁶

Paroxetine. Fifteen adults with profound mental retardation (including seven with pervasive developmental disorders) received paroxetine, 10 to 50 mg/d (mean 35 mg/d) in a 4-month open-label trial. Frequency and severity of aggression were rated as improved after 1 month, but not at 4 months.¹⁷

Mirtazapine. In an open-label trial, 26 patients ages 3 to 23 with pervasive developmental disorders were treated with mirtazapine, 7.5 to 45 mg/d (mean 30.3 mg/d). Aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia decreased in 9 patients (34%), as determined by ratings of “much improved” or “very much improved” on the CGI. Adverse effects included increased appetite and transient sedation.¹⁸

Mood stabilizers

Lithium. No recent studies of lithium in pervasive developmental disorders are known to exist, but several case reports have been published:

• two reports found lithium decreased manic symptoms in individuals with autism and a family history of bipolar disorder^19,20
• one report of lithium augmentation of fluvoxamine in an adult with autistic disorder noted markedly improved aggression and impulsivity after 2 weeks of treatment, as measured by the CGI, Brown Aggression Scale, and Vineland Adaptive Behavior Scale.²¹

Divalproex. In an open-label trial, 14 subjects ages 5 to 40 with pervasive developmental disorders were given divalproex sodium, 125 to 2,500 mg/d (mean 768 mg/d; mean blood level 75.8 mcg/mL. Affective instability, repetitive behavior, impulsivity, and aggression improved in 10 patients (71%), as measured by CGI ratings of “much improved” or “very much improved.”²² Adverse effects included sedation, weight gain, hair loss, behavioral activation, and elevated liver enzymes.

Lamotrigine. In a 4-week, double-blind, placebo-controlled trial, lamotrigine, 5.0 mg/kg/d, was given to 14 children ages 3 to 11 with autistic disorder.²³ Lamotrigine and placebo showed no significant differences in effect, as measured by the ABC, Autism Behavior Checklist, Vineland scales, Childhood Autism Rating Scale, and PreLinguistic Autism Diagnostic Observation Scale. Insomnia and hyperactivity were the most common adverse effects.

α2-adrenergic agonists

Clonidine. Jaselskis et al administered clonidine, 4 to 10 mcg/kg/d, to eight children ages 5 to 13 with autism in a 6-week, double-blind, placebo-controlled, crossover study.²⁴ Symptoms of hyperactivity, irritability, and oppositional behavior improved, as determined by teacher ratings on the ABC, Conners Abbreviated Parent-Teacher Questionnaire, and Attention Deficit Disorder with Hyperactivity Comprehensive Teacher’s Rating Scale. Adverse effects included hypotension, sedation, and decreased activity.

Nine autistic patients ages 5 to 33 received transdermal clonidine, 0.16 to 0.48 mcg/kg/d (mean 3.6 mcg/kg/d), in a 4-week, double-blind, placebo-controlled, crossover study. Hyperarousal, impulsivity, and self-stimulation improved, as measured by the Ritvo-Freeman Real Life Rating Scale and the CGI. Sedation and fatigue were reported, especially during the first 2 weeks of treatment.²⁵

Guanfacine. The effect of guanfacine, 0.25 to 9.0 mg/d (mean 2.6 mg/d), was examined retrospectively in 80 children and adolescents ages 3 to 18 with pervasive developmental disorders.²⁶ Hyperactivity, inattention, and tics improved in the 19 subjects (23.8%) who were rated “much improved” or “very much improved” on the CGI. Sedation was the most frequently reported adverse effect.

Psychostimulants

Early reports showed little benefit from stimulants in pervasive developmental disorders, but more recent studies suggest a modest effect. The RUPP Autism Network is conducting a large controlled investigation of methylphenidate to better understand the role of stimulants in children and adolescents in this diagnostic cluster.

 

Quintana et al conducted a double-blind, crossover study of methylphenidate, 10 or 20 mg bid for 2 weeks, in 10 children ages 7 to 11 with autism.²⁷ Although irritability and hyperactivity showed statistically significant improvement as determined by the ABC and Conners Teacher Questionnaire, the authors reported only modest clinical effects. More recently, use of methylphenidate, 0.3 and 0.6 mg/kg/dose, was associated with a 50% decrease on the Connors Hyperactivity Index in 8 of 13 autistic children ages 5 to 11.²⁸ Adverse effects—most common with the 0.6 mg/kg/dose—included social withdrawal and irritability in this double-blind, placebo-controlled, crossover study.

Related resources

• McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, Charney DS, Leckman JF (eds). Pediatric psychopharmacology: Principles and practice. New York: Oxford University Press, 2002.
• Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• National Institute of Mental Health. Autism booklet. www.nimh.nih.gov/publicat/autism.cfm
• Autism Society of America. www.autism-society.org

Drug brand names

• Clomipramine • Anafranil
• Clonidine • Catapres
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guanfacine • Tenex
• Lamotrigine • Lamictal
• Lithium • Eskalith
• Methylphenidate • Ritalin
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

Dr. Stigler reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Posey receives grant support from and is a consultant to Eli Lilly & Co.

Dr. McDougle receives grant support from and is a consultant to Pfizer Inc., Eli Lilly & Co., and Janssen Pharmaceutica, and is a speaker for Pfizer Inc. and Janssen Pharmaceutica.

Acknowledgments

This work was supported in part by a Daniel X. Freedman Psychiatric Research Fellowship Award (Dr. Posey), a National Alliance for Research in Schizophrenia and Depression Young Investigator Award (Dr. Posey), a Research Unit on Pediatric Psychopharmacology contract (N01MH70001) from the National Institute of Mental Health to Indiana University (Drs. McDougle and Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development grant (B-01-SP-IN-0200).

Aggression, irritability, repetitive phenomena, or hyperactivity can interfere with the education and treatment of patients with autism.¹ To assist clinicians in selecting drug therapies to control these behaviors, we developed a medication strategy based on controlled studies and our experience in an autism specialty clinic. In this article, we:

• offer an overview with two algorithms that show how to target maladaptive behaviors in patients of all ages with autism
• and discuss the controlled clinical evidence behind this approach.

Targeting behaviors

A multimodal approach is used to manage autistic disorder. Although behavioral techniques are useful and may decrease the need for drug therapy, one or more medications are often required to target severe maladaptive behaviors. Although we recommend that you consider all interfering behaviors when selecting medications, it is important to:

• initially focus on symptoms—such as self-injurious behaviors and aggression—that acutely affect the patient’s and caregiver’s safety
• consider the patient as being pre- or postpubertal, as developmental level may affect medication response.

Figure 1 BEHAVIOR-BASED DRUG THERAPY FOR CHILDREN WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc. Aggression or self-injury. When drug therapy is needed to control severe aggression or self-injurious behavior, we recommend a trial of an atypical antipsychotic for prepubertal patients (Figure 1). Alternately, you may consider a mood stabilizer such as lithium or divalproex for an adult patient with prominent symptoms (Figure 2). However, mood stabilizer use requires monitoring by venipuncture for potential blood cell or liver function abnormalities.

Atypical antipsychotics are associated with adverse effects including sedation, weight gain, extrapyramidal symptoms, tardive dyskinesia, and hyperprolactinemia. Therefore, you may need to monitor weight, lipid profile, glucose, liver function, and cardiac function when using this class of agent.

Repetitive phenomena can be addressed with selective serotonin reuptake inhibitors (SSRIs), although SSRIs may be activating in children and tend to be better tolerated in older adolescents and adults.

Anxiety. In children with anxiety, we suggest a trial of mirtazapine—because of its calming properties—before you try an SSRI. If both the SSRI and mirtazapine are ineffective, try an α2-adrenergic agonist. A baseline ECG is recommended before starting an α2-adrenergic agonist—particularly clonidine, which has been associated with rare cardiovascular events. Overall, these agents are well tolerated.

Hyperactivity, inattention. Anecdotal evidence indicates that stimulants may worsen symptoms of aggression, hyperactivity, and irritability in individuals with autism. Therefore, we suggest you start with an α2-adrenergic agonist when target symptoms include hyperactivity and inattention. Consider a stimulant trial if the α2-adrenergic agonist does not control the symptoms.

An atypical antipsychotic is generally recommended for autistic individuals with treatment-resistant hyperactivity and inattention, anxiety, and interfering repetitive behaviors.

Drug therapy. As summarized below, controlled evidence for behavior-based drug therapy of autism (Table.) suggests a role for antipsychotics, antidepressants, mood stabilizers, and psychostimulants in managing interfering behaviors.

Antipsychotics

Risperidone. Two controlled studies have reported the effect of risperidone on autism’s related symptoms.

McDougle et al conducted a 12-week, double-blind, placebo-controlled trial of risperidone, mean 2.9 mg/d, in adults with pervasive developmental disorders.² Repetitive behavior, aggression, anxiety, irritability, depression, and general behavioral symptoms decreased in 8 of 14 patients, as measured by Clinical Global Impressions (CGI) scale ratings of “much improved” or “very much improved.” Sixteen subjects who received placebo showed no response. Transient sedation was the most common adverse effect.

More recently, the National Institutes of Mental Health-sponsored Research Units on Pediatric Psychopharmacology (RUPP) Autism Network completed a double-blind, placebo-controlled study of risperidone, 0.5 to 3.5 mg/d (mean 1.8 mg/d), in 101 children and adolescents with autism.³ After 8 weeks, 69% of the risperidone group responded, compared with 12% of the placebo group. Response was defined as:

• at least a 25% decrease in the Irritability subscale score of the Aberrant Behavior Checklist (ABC)
• and CGI ratings of “much improved” or “very much improved.”

Risperidone was effective for treating aggression, agitation, hyperactivity, and repetitive behavior. Adverse effects included weight gain (mean 2.7 kg vs. 0.8 kg with placebo), increased appetite, sedation, dizziness, and hypersalivation.

Olanzapine. A 12-week, open-label study of olanzapine, mean 7.8 mg/d, was conducted in eight patients ages 5 to 42 diagnosed with a pervasive developmental disorder.⁴ Hyperactivity, social relatedness, self-injurious behavior, aggression, anxiety, and depression improved significantly in six of seven patients who completed the trial, as measured by a CGI classification of “much improved” or “very much improved.” Adverse effects included weight gain (mean 18.4 lbs) in six patients and sedation in three.

 

Malone et al conducted a 6-week, open-label comparison of olanzapine, mean 7.9 mg/d, versus haloperidol, mean 1.4 mg/d, in 12 children with autistic disorder.⁵ Five of six subjects who received olanzapine responded, compared with three of six who received haloperidol, as determined by a CGI classification of “much improved” or “very much improved.” Anger/uncooperativeness and hyperactivity were reduced significantly only in the olanzapine group. Weight gain and sedation were the most common adverse effects with both medications. Weight gain was greater with olanzapine (mean 9 lbs) than with haloperidol (mean 3.2 lbs).

Quetiapine. Only one report addresses quetiapine in children and adolescents with autism.⁶ Two of six patients completed this 16-week, open-label trial of quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/d). The group showed no statistically significant improvement in behavioral symptoms. Two patients achieved CGI ratings of “much improved” or “very much improved.” One subject dropped out after a possible seizure during treatment, and three others withdrew because of sedation or lack of response.

Ziprasidone. McDougle et al conducted a naturalistic, open-label study of ziprasidone, 20 to 120 mg/d (mean 59.2 mg/d), in 12 subjects ages 8 to 20. Nine were diagnosed with autism and three with a pervasive developmental disorder not otherwise specified (NOS). Six subjects responded across 14 weeks of treatment, as determined by ratings of “much improved” or “very much improved” on the CGI.⁷

Transient sedation was the most common adverse effect. Mean weight change was −5.83 lbs (range −35 to +6 lbs). Despite ziprasidone’s reported risk of causing abnormal cardiac rhythms, no cardiovascular adverse effects were reported.

Clozapine. Three case reports but no controlled studies have addressed clozapine in autistic disorder:

• Zuddas et al used clozapine, 100 to 200 mg/d for 3 months, to treat three children ages 8 to 12.⁸ Previous trials of haloperidol were ineffective, but the patients’ aggression, hyperactivity, negativism, and language and communication skills improved with clozapine, as measured by the Children’s Psychiatric Rating Scale (CPRS) and the Self-Injurious Behavior Questionnaire.
• Chen et al used clozapine, 275 mg/d, to treat a 17-year-old male inpatient.⁹ Aggression was significantly reduced across 15 days, as determined by a 21-question modified version of the CPRS. Side effects included mild constipation and excessive salivation.
• Clozapine, 300 mg/d for 2 months, reduced aggression in an adult patient and was associated with progressive and marked improvement of aggression and social interaction, as measured by the CGI and the Visual Analog Scale (VAS). No agranulocytosis or extrapyramidal symptoms were observed across 5 years of therapy.¹⁰

Clozapine’s adverse effect profile probably explains why the literature contains so little data regarding its use in patients with autism. This drug’s propensity to lower the seizure threshold discourages its use in a population predisposed to seizures. Autistic patients also have a low tolerance for frequent venipuncture and limited ability to communicate agranulocytosis symptoms.

Antidepressants

Clomipramine—a tricyclic antidepressant with anti-obsessional properties—has shown some positive effects in treating autistic behaviors. Even so, this compound is prescribed infrequently to patients with autism because of low tolerability. In one recent double-blind, placebo-controlled, crossover study, 36 autistic patients ages 10 to 36 received:

• clomipramine, 100 to 150 mg/d (mean 128 mg/d)
• haloperidol, 1 to 1.5 mg/d (mean 1.3 mg/d)

or placebo for 7 weeks. Among patients who completed the trial, clomipramine and haloperidol were similarly effective in reducing overall autistic symptoms, irritability, and stereotypy. However, only 37.5% of those receiving clomipramine completed the study because of adverse effects, behavioral problems, and general lack of efficacy.¹¹

Table

CONTROLLED EVIDENCE* FOR BEHAVIOR-BASED DRUG THERAPY OF AUTISM

Medication	Behaviors improved	Significant adverse effects	Comments
Risperidone 2	Aggression, irritability	Mild transient sedation	Conducted in adults
Risperidone 3	Aggression, irritability	Weight gain, increased appetite, sedation, tremor, hypersalivation	Largest controlled study to date in children with autism
Clomipramine 11	Irritability, stereotypy	Tachycardia, tremors, diaphoresis, insomnia, nausea	Conducted in children and adults
Fluvoxamine 12	Aggression, repetitive phenomena	Nausea, sedation	No published controlled pediatric data; unpublished pediatric data unfavorable
Clonidine 24	Hyperactivity, irritability, stereotypies, oppositional behavior, aggression, self-injury	Hypotension, sedation, decreased activity	Small number of subjects
Clonidine 25	Impulsivity, self-stimulation, hyperarousal	Sedation and fatigue	Small number of subjects
Methylphenidate 28	Hyperactivity, irritability	Social withdrawal and irritability	Adverse effects more common at 0.6 mg/kg/dose
• Double-blind, placebo-controlled studies

Fluvoxamine. Only one double-blind, placebo-controlled study has examined the use of an SSRI in autistic disorder.¹² In this 12-week trial, 30 adults with autism received fluvoxamine, mean 276.7 mg/d, or placebo. Eight of 15 subjects in the fluvoxamine group were categorized as “much improved” or “very much improved” on the CGI.

Fluvoxamine was much more effective than placebo in reducing repetitive thoughts and behavior, aggression, and maladaptive behavior. Adverse effects included minimal sedation and nausea.

Unpublished data of McDougle et al suggest that autistic children and adolescents respond less favorably than adults to fluvoxamine. In a 12-week, double-blind, placebocontrolled trial in patients ages 5 to 18, only 1 of 18 subjects responded to fluvoxamine at a mean dosage of 106.9 mg/d. Agitation, increased aggression, hyperactivity, and increased repetitive behavior were reported.

 

Fluoxetine. Seven autistic patients ages 9 to 20 were treated with fluoxetine, 20 to 80 mg/d (mean 37.1 mg/d) in an 18-month longitudinal open trial. Irritability, lethargy, and stereotypy improved, as measured by the ABC.¹³ Adverse effects included increased hyperactivity and transient appetite suppression.

In another open-label trial of 37 autistic children ages 2 to 7, response was rated by investigators as “excellent” in 11 and “good” in another 11 who received fluoxetine, 0.2 to 1.4 mg/kg/d. However, aggression was a frequent cause for drug discontinuation during the 21-month study.¹⁴

Sertraline. In an open-label trial, Steingard et al treated nine autistic children ages 6 to 12 with sertraline, 25 to 50 mg/d for 2 to 8 weeks. Clinical improvement was observed in irritability, transition-associated anxiety, and need for sameness in eight of the children.¹⁵

Figure 2 BEHAVIOR-BASED DRUG THERAPY FOR POSTPUBERTAL PATIENTS WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc.In an open-label trial, 42 adults with pervasive developmental disorders were treated for 12 weeks with sertraline, 50 to 200 mg/d (mean 122 mg/d). Twenty-four (57%) achieved CGI ratings of “much improved” or “very much improved” in aggressive and repetitive behavior.¹⁶

Paroxetine. Fifteen adults with profound mental retardation (including seven with pervasive developmental disorders) received paroxetine, 10 to 50 mg/d (mean 35 mg/d) in a 4-month open-label trial. Frequency and severity of aggression were rated as improved after 1 month, but not at 4 months.¹⁷

Mirtazapine. In an open-label trial, 26 patients ages 3 to 23 with pervasive developmental disorders were treated with mirtazapine, 7.5 to 45 mg/d (mean 30.3 mg/d). Aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia decreased in 9 patients (34%), as determined by ratings of “much improved” or “very much improved” on the CGI. Adverse effects included increased appetite and transient sedation.¹⁸

Mood stabilizers

Lithium. No recent studies of lithium in pervasive developmental disorders are known to exist, but several case reports have been published:

• two reports found lithium decreased manic symptoms in individuals with autism and a family history of bipolar disorder^19,20
• one report of lithium augmentation of fluvoxamine in an adult with autistic disorder noted markedly improved aggression and impulsivity after 2 weeks of treatment, as measured by the CGI, Brown Aggression Scale, and Vineland Adaptive Behavior Scale.²¹

Divalproex. In an open-label trial, 14 subjects ages 5 to 40 with pervasive developmental disorders were given divalproex sodium, 125 to 2,500 mg/d (mean 768 mg/d; mean blood level 75.8 mcg/mL. Affective instability, repetitive behavior, impulsivity, and aggression improved in 10 patients (71%), as measured by CGI ratings of “much improved” or “very much improved.”²² Adverse effects included sedation, weight gain, hair loss, behavioral activation, and elevated liver enzymes.

Lamotrigine. In a 4-week, double-blind, placebo-controlled trial, lamotrigine, 5.0 mg/kg/d, was given to 14 children ages 3 to 11 with autistic disorder.²³ Lamotrigine and placebo showed no significant differences in effect, as measured by the ABC, Autism Behavior Checklist, Vineland scales, Childhood Autism Rating Scale, and PreLinguistic Autism Diagnostic Observation Scale. Insomnia and hyperactivity were the most common adverse effects.

α2-adrenergic agonists

Clonidine. Jaselskis et al administered clonidine, 4 to 10 mcg/kg/d, to eight children ages 5 to 13 with autism in a 6-week, double-blind, placebo-controlled, crossover study.²⁴ Symptoms of hyperactivity, irritability, and oppositional behavior improved, as determined by teacher ratings on the ABC, Conners Abbreviated Parent-Teacher Questionnaire, and Attention Deficit Disorder with Hyperactivity Comprehensive Teacher’s Rating Scale. Adverse effects included hypotension, sedation, and decreased activity.

Nine autistic patients ages 5 to 33 received transdermal clonidine, 0.16 to 0.48 mcg/kg/d (mean 3.6 mcg/kg/d), in a 4-week, double-blind, placebo-controlled, crossover study. Hyperarousal, impulsivity, and self-stimulation improved, as measured by the Ritvo-Freeman Real Life Rating Scale and the CGI. Sedation and fatigue were reported, especially during the first 2 weeks of treatment.²⁵

Guanfacine. The effect of guanfacine, 0.25 to 9.0 mg/d (mean 2.6 mg/d), was examined retrospectively in 80 children and adolescents ages 3 to 18 with pervasive developmental disorders.²⁶ Hyperactivity, inattention, and tics improved in the 19 subjects (23.8%) who were rated “much improved” or “very much improved” on the CGI. Sedation was the most frequently reported adverse effect.

Psychostimulants

Early reports showed little benefit from stimulants in pervasive developmental disorders, but more recent studies suggest a modest effect. The RUPP Autism Network is conducting a large controlled investigation of methylphenidate to better understand the role of stimulants in children and adolescents in this diagnostic cluster.

 

Quintana et al conducted a double-blind, crossover study of methylphenidate, 10 or 20 mg bid for 2 weeks, in 10 children ages 7 to 11 with autism.²⁷ Although irritability and hyperactivity showed statistically significant improvement as determined by the ABC and Conners Teacher Questionnaire, the authors reported only modest clinical effects. More recently, use of methylphenidate, 0.3 and 0.6 mg/kg/dose, was associated with a 50% decrease on the Connors Hyperactivity Index in 8 of 13 autistic children ages 5 to 11.²⁸ Adverse effects—most common with the 0.6 mg/kg/dose—included social withdrawal and irritability in this double-blind, placebo-controlled, crossover study.

Related resources

• McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, Charney DS, Leckman JF (eds). Pediatric psychopharmacology: Principles and practice. New York: Oxford University Press, 2002.
• Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• National Institute of Mental Health. Autism booklet. www.nimh.nih.gov/publicat/autism.cfm
• Autism Society of America. www.autism-society.org

Drug brand names

• Clomipramine • Anafranil
• Clonidine • Catapres
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guanfacine • Tenex
• Lamotrigine • Lamictal
• Lithium • Eskalith
• Methylphenidate • Ritalin
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

Dr. Stigler reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Posey receives grant support from and is a consultant to Eli Lilly & Co.

Dr. McDougle receives grant support from and is a consultant to Pfizer Inc., Eli Lilly & Co., and Janssen Pharmaceutica, and is a speaker for Pfizer Inc. and Janssen Pharmaceutica.

Acknowledgments

This work was supported in part by a Daniel X. Freedman Psychiatric Research Fellowship Award (Dr. Posey), a National Alliance for Research in Schizophrenia and Depression Young Investigator Award (Dr. Posey), a Research Unit on Pediatric Psychopharmacology contract (N01MH70001) from the National Institute of Mental Health to Indiana University (Drs. McDougle and Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development grant (B-01-SP-IN-0200).

Aggression, irritability, repetitive phenomena, or hyperactivity can interfere with the education and treatment of patients with autism.¹ To assist clinicians in selecting drug therapies to control these behaviors, we developed a medication strategy based on controlled studies and our experience in an autism specialty clinic. In this article, we:

• offer an overview with two algorithms that show how to target maladaptive behaviors in patients of all ages with autism
• and discuss the controlled clinical evidence behind this approach.

Targeting behaviors

A multimodal approach is used to manage autistic disorder. Although behavioral techniques are useful and may decrease the need for drug therapy, one or more medications are often required to target severe maladaptive behaviors. Although we recommend that you consider all interfering behaviors when selecting medications, it is important to:

• initially focus on symptoms—such as self-injurious behaviors and aggression—that acutely affect the patient’s and caregiver’s safety
• consider the patient as being pre- or postpubertal, as developmental level may affect medication response.

Figure 1 BEHAVIOR-BASED DRUG THERAPY FOR CHILDREN WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc. Aggression or self-injury. When drug therapy is needed to control severe aggression or self-injurious behavior, we recommend a trial of an atypical antipsychotic for prepubertal patients (Figure 1). Alternately, you may consider a mood stabilizer such as lithium or divalproex for an adult patient with prominent symptoms (Figure 2). However, mood stabilizer use requires monitoring by venipuncture for potential blood cell or liver function abnormalities.

Atypical antipsychotics are associated with adverse effects including sedation, weight gain, extrapyramidal symptoms, tardive dyskinesia, and hyperprolactinemia. Therefore, you may need to monitor weight, lipid profile, glucose, liver function, and cardiac function when using this class of agent.

Repetitive phenomena can be addressed with selective serotonin reuptake inhibitors (SSRIs), although SSRIs may be activating in children and tend to be better tolerated in older adolescents and adults.

Anxiety. In children with anxiety, we suggest a trial of mirtazapine—because of its calming properties—before you try an SSRI. If both the SSRI and mirtazapine are ineffective, try an α2-adrenergic agonist. A baseline ECG is recommended before starting an α2-adrenergic agonist—particularly clonidine, which has been associated with rare cardiovascular events. Overall, these agents are well tolerated.

Hyperactivity, inattention. Anecdotal evidence indicates that stimulants may worsen symptoms of aggression, hyperactivity, and irritability in individuals with autism. Therefore, we suggest you start with an α2-adrenergic agonist when target symptoms include hyperactivity and inattention. Consider a stimulant trial if the α2-adrenergic agonist does not control the symptoms.

An atypical antipsychotic is generally recommended for autistic individuals with treatment-resistant hyperactivity and inattention, anxiety, and interfering repetitive behaviors.

Drug therapy. As summarized below, controlled evidence for behavior-based drug therapy of autism (Table.) suggests a role for antipsychotics, antidepressants, mood stabilizers, and psychostimulants in managing interfering behaviors.

Antipsychotics

Risperidone. Two controlled studies have reported the effect of risperidone on autism’s related symptoms.

McDougle et al conducted a 12-week, double-blind, placebo-controlled trial of risperidone, mean 2.9 mg/d, in adults with pervasive developmental disorders.² Repetitive behavior, aggression, anxiety, irritability, depression, and general behavioral symptoms decreased in 8 of 14 patients, as measured by Clinical Global Impressions (CGI) scale ratings of “much improved” or “very much improved.” Sixteen subjects who received placebo showed no response. Transient sedation was the most common adverse effect.

More recently, the National Institutes of Mental Health-sponsored Research Units on Pediatric Psychopharmacology (RUPP) Autism Network completed a double-blind, placebo-controlled study of risperidone, 0.5 to 3.5 mg/d (mean 1.8 mg/d), in 101 children and adolescents with autism.³ After 8 weeks, 69% of the risperidone group responded, compared with 12% of the placebo group. Response was defined as:

• at least a 25% decrease in the Irritability subscale score of the Aberrant Behavior Checklist (ABC)
• and CGI ratings of “much improved” or “very much improved.”

Risperidone was effective for treating aggression, agitation, hyperactivity, and repetitive behavior. Adverse effects included weight gain (mean 2.7 kg vs. 0.8 kg with placebo), increased appetite, sedation, dizziness, and hypersalivation.

Olanzapine. A 12-week, open-label study of olanzapine, mean 7.8 mg/d, was conducted in eight patients ages 5 to 42 diagnosed with a pervasive developmental disorder.⁴ Hyperactivity, social relatedness, self-injurious behavior, aggression, anxiety, and depression improved significantly in six of seven patients who completed the trial, as measured by a CGI classification of “much improved” or “very much improved.” Adverse effects included weight gain (mean 18.4 lbs) in six patients and sedation in three.

 

Malone et al conducted a 6-week, open-label comparison of olanzapine, mean 7.9 mg/d, versus haloperidol, mean 1.4 mg/d, in 12 children with autistic disorder.⁵ Five of six subjects who received olanzapine responded, compared with three of six who received haloperidol, as determined by a CGI classification of “much improved” or “very much improved.” Anger/uncooperativeness and hyperactivity were reduced significantly only in the olanzapine group. Weight gain and sedation were the most common adverse effects with both medications. Weight gain was greater with olanzapine (mean 9 lbs) than with haloperidol (mean 3.2 lbs).

Quetiapine. Only one report addresses quetiapine in children and adolescents with autism.⁶ Two of six patients completed this 16-week, open-label trial of quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/d). The group showed no statistically significant improvement in behavioral symptoms. Two patients achieved CGI ratings of “much improved” or “very much improved.” One subject dropped out after a possible seizure during treatment, and three others withdrew because of sedation or lack of response.

Ziprasidone. McDougle et al conducted a naturalistic, open-label study of ziprasidone, 20 to 120 mg/d (mean 59.2 mg/d), in 12 subjects ages 8 to 20. Nine were diagnosed with autism and three with a pervasive developmental disorder not otherwise specified (NOS). Six subjects responded across 14 weeks of treatment, as determined by ratings of “much improved” or “very much improved” on the CGI.⁷

Transient sedation was the most common adverse effect. Mean weight change was −5.83 lbs (range −35 to +6 lbs). Despite ziprasidone’s reported risk of causing abnormal cardiac rhythms, no cardiovascular adverse effects were reported.

Clozapine. Three case reports but no controlled studies have addressed clozapine in autistic disorder:

• Zuddas et al used clozapine, 100 to 200 mg/d for 3 months, to treat three children ages 8 to 12.⁸ Previous trials of haloperidol were ineffective, but the patients’ aggression, hyperactivity, negativism, and language and communication skills improved with clozapine, as measured by the Children’s Psychiatric Rating Scale (CPRS) and the Self-Injurious Behavior Questionnaire.
• Chen et al used clozapine, 275 mg/d, to treat a 17-year-old male inpatient.⁹ Aggression was significantly reduced across 15 days, as determined by a 21-question modified version of the CPRS. Side effects included mild constipation and excessive salivation.
• Clozapine, 300 mg/d for 2 months, reduced aggression in an adult patient and was associated with progressive and marked improvement of aggression and social interaction, as measured by the CGI and the Visual Analog Scale (VAS). No agranulocytosis or extrapyramidal symptoms were observed across 5 years of therapy.¹⁰

Clozapine’s adverse effect profile probably explains why the literature contains so little data regarding its use in patients with autism. This drug’s propensity to lower the seizure threshold discourages its use in a population predisposed to seizures. Autistic patients also have a low tolerance for frequent venipuncture and limited ability to communicate agranulocytosis symptoms.

Antidepressants

Clomipramine—a tricyclic antidepressant with anti-obsessional properties—has shown some positive effects in treating autistic behaviors. Even so, this compound is prescribed infrequently to patients with autism because of low tolerability. In one recent double-blind, placebo-controlled, crossover study, 36 autistic patients ages 10 to 36 received:

• clomipramine, 100 to 150 mg/d (mean 128 mg/d)
• haloperidol, 1 to 1.5 mg/d (mean 1.3 mg/d)

or placebo for 7 weeks. Among patients who completed the trial, clomipramine and haloperidol were similarly effective in reducing overall autistic symptoms, irritability, and stereotypy. However, only 37.5% of those receiving clomipramine completed the study because of adverse effects, behavioral problems, and general lack of efficacy.¹¹

Table

CONTROLLED EVIDENCE* FOR BEHAVIOR-BASED DRUG THERAPY OF AUTISM

Medication	Behaviors improved	Significant adverse effects	Comments
Risperidone 2	Aggression, irritability	Mild transient sedation	Conducted in adults
Risperidone 3	Aggression, irritability	Weight gain, increased appetite, sedation, tremor, hypersalivation	Largest controlled study to date in children with autism
Clomipramine 11	Irritability, stereotypy	Tachycardia, tremors, diaphoresis, insomnia, nausea	Conducted in children and adults
Fluvoxamine 12	Aggression, repetitive phenomena	Nausea, sedation	No published controlled pediatric data; unpublished pediatric data unfavorable
Clonidine 24	Hyperactivity, irritability, stereotypies, oppositional behavior, aggression, self-injury	Hypotension, sedation, decreased activity	Small number of subjects
Clonidine 25	Impulsivity, self-stimulation, hyperarousal	Sedation and fatigue	Small number of subjects
Methylphenidate 28	Hyperactivity, irritability	Social withdrawal and irritability	Adverse effects more common at 0.6 mg/kg/dose
• Double-blind, placebo-controlled studies

Fluvoxamine. Only one double-blind, placebo-controlled study has examined the use of an SSRI in autistic disorder.¹² In this 12-week trial, 30 adults with autism received fluvoxamine, mean 276.7 mg/d, or placebo. Eight of 15 subjects in the fluvoxamine group were categorized as “much improved” or “very much improved” on the CGI.

Fluvoxamine was much more effective than placebo in reducing repetitive thoughts and behavior, aggression, and maladaptive behavior. Adverse effects included minimal sedation and nausea.

Unpublished data of McDougle et al suggest that autistic children and adolescents respond less favorably than adults to fluvoxamine. In a 12-week, double-blind, placebocontrolled trial in patients ages 5 to 18, only 1 of 18 subjects responded to fluvoxamine at a mean dosage of 106.9 mg/d. Agitation, increased aggression, hyperactivity, and increased repetitive behavior were reported.

 

Fluoxetine. Seven autistic patients ages 9 to 20 were treated with fluoxetine, 20 to 80 mg/d (mean 37.1 mg/d) in an 18-month longitudinal open trial. Irritability, lethargy, and stereotypy improved, as measured by the ABC.¹³ Adverse effects included increased hyperactivity and transient appetite suppression.

In another open-label trial of 37 autistic children ages 2 to 7, response was rated by investigators as “excellent” in 11 and “good” in another 11 who received fluoxetine, 0.2 to 1.4 mg/kg/d. However, aggression was a frequent cause for drug discontinuation during the 21-month study.¹⁴

Sertraline. In an open-label trial, Steingard et al treated nine autistic children ages 6 to 12 with sertraline, 25 to 50 mg/d for 2 to 8 weeks. Clinical improvement was observed in irritability, transition-associated anxiety, and need for sameness in eight of the children.¹⁵

Figure 2 BEHAVIOR-BASED DRUG THERAPY FOR POSTPUBERTAL PATIENTS WITH AUTISM

Source: Reprinted with permission from McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, et al (eds). Pediatric psychopharmacology: principles and practice. New York: Oxford University Press, 2002. Copyright © 2002 by Oxford University Press, Inc.In an open-label trial, 42 adults with pervasive developmental disorders were treated for 12 weeks with sertraline, 50 to 200 mg/d (mean 122 mg/d). Twenty-four (57%) achieved CGI ratings of “much improved” or “very much improved” in aggressive and repetitive behavior.¹⁶

Paroxetine. Fifteen adults with profound mental retardation (including seven with pervasive developmental disorders) received paroxetine, 10 to 50 mg/d (mean 35 mg/d) in a 4-month open-label trial. Frequency and severity of aggression were rated as improved after 1 month, but not at 4 months.¹⁷

Mirtazapine. In an open-label trial, 26 patients ages 3 to 23 with pervasive developmental disorders were treated with mirtazapine, 7.5 to 45 mg/d (mean 30.3 mg/d). Aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia decreased in 9 patients (34%), as determined by ratings of “much improved” or “very much improved” on the CGI. Adverse effects included increased appetite and transient sedation.¹⁸

Mood stabilizers

Lithium. No recent studies of lithium in pervasive developmental disorders are known to exist, but several case reports have been published:

• two reports found lithium decreased manic symptoms in individuals with autism and a family history of bipolar disorder^19,20
• one report of lithium augmentation of fluvoxamine in an adult with autistic disorder noted markedly improved aggression and impulsivity after 2 weeks of treatment, as measured by the CGI, Brown Aggression Scale, and Vineland Adaptive Behavior Scale.²¹

Divalproex. In an open-label trial, 14 subjects ages 5 to 40 with pervasive developmental disorders were given divalproex sodium, 125 to 2,500 mg/d (mean 768 mg/d; mean blood level 75.8 mcg/mL. Affective instability, repetitive behavior, impulsivity, and aggression improved in 10 patients (71%), as measured by CGI ratings of “much improved” or “very much improved.”²² Adverse effects included sedation, weight gain, hair loss, behavioral activation, and elevated liver enzymes.

Lamotrigine. In a 4-week, double-blind, placebo-controlled trial, lamotrigine, 5.0 mg/kg/d, was given to 14 children ages 3 to 11 with autistic disorder.²³ Lamotrigine and placebo showed no significant differences in effect, as measured by the ABC, Autism Behavior Checklist, Vineland scales, Childhood Autism Rating Scale, and PreLinguistic Autism Diagnostic Observation Scale. Insomnia and hyperactivity were the most common adverse effects.

α2-adrenergic agonists

Clonidine. Jaselskis et al administered clonidine, 4 to 10 mcg/kg/d, to eight children ages 5 to 13 with autism in a 6-week, double-blind, placebo-controlled, crossover study.²⁴ Symptoms of hyperactivity, irritability, and oppositional behavior improved, as determined by teacher ratings on the ABC, Conners Abbreviated Parent-Teacher Questionnaire, and Attention Deficit Disorder with Hyperactivity Comprehensive Teacher’s Rating Scale. Adverse effects included hypotension, sedation, and decreased activity.

Nine autistic patients ages 5 to 33 received transdermal clonidine, 0.16 to 0.48 mcg/kg/d (mean 3.6 mcg/kg/d), in a 4-week, double-blind, placebo-controlled, crossover study. Hyperarousal, impulsivity, and self-stimulation improved, as measured by the Ritvo-Freeman Real Life Rating Scale and the CGI. Sedation and fatigue were reported, especially during the first 2 weeks of treatment.²⁵

Guanfacine. The effect of guanfacine, 0.25 to 9.0 mg/d (mean 2.6 mg/d), was examined retrospectively in 80 children and adolescents ages 3 to 18 with pervasive developmental disorders.²⁶ Hyperactivity, inattention, and tics improved in the 19 subjects (23.8%) who were rated “much improved” or “very much improved” on the CGI. Sedation was the most frequently reported adverse effect.

Psychostimulants

Early reports showed little benefit from stimulants in pervasive developmental disorders, but more recent studies suggest a modest effect. The RUPP Autism Network is conducting a large controlled investigation of methylphenidate to better understand the role of stimulants in children and adolescents in this diagnostic cluster.

 

Quintana et al conducted a double-blind, crossover study of methylphenidate, 10 or 20 mg bid for 2 weeks, in 10 children ages 7 to 11 with autism.²⁷ Although irritability and hyperactivity showed statistically significant improvement as determined by the ABC and Conners Teacher Questionnaire, the authors reported only modest clinical effects. More recently, use of methylphenidate, 0.3 and 0.6 mg/kg/dose, was associated with a 50% decrease on the Connors Hyperactivity Index in 8 of 13 autistic children ages 5 to 11.²⁸ Adverse effects—most common with the 0.6 mg/kg/dose—included social withdrawal and irritability in this double-blind, placebo-controlled, crossover study.

Related resources

• McDougle CJ, Posey DJ. Autistic and other pervasive developmental disorders. In: Martin A, Scahill L, Charney DS, Leckman JF (eds). Pediatric psychopharmacology: Principles and practice. New York: Oxford University Press, 2002.
• Davis KL, Charney D, Coyle JT, Nemeroff C (eds). Neuropsychopharmacology: the fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins, 2002.
• National Institute of Mental Health. Autism booklet. www.nimh.nih.gov/publicat/autism.cfm
• Autism Society of America. www.autism-society.org

Drug brand names

• Clomipramine • Anafranil
• Clonidine • Catapres
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guanfacine • Tenex
• Lamotrigine • Lamictal
• Lithium • Eskalith
• Methylphenidate • Ritalin
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

Dr. Stigler reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Posey receives grant support from and is a consultant to Eli Lilly & Co.

Dr. McDougle receives grant support from and is a consultant to Pfizer Inc., Eli Lilly & Co., and Janssen Pharmaceutica, and is a speaker for Pfizer Inc. and Janssen Pharmaceutica.

Acknowledgments

This work was supported in part by a Daniel X. Freedman Psychiatric Research Fellowship Award (Dr. Posey), a National Alliance for Research in Schizophrenia and Depression Young Investigator Award (Dr. Posey), a Research Unit on Pediatric Psychopharmacology contract (N01MH70001) from the National Institute of Mental Health to Indiana University (Drs. McDougle and Posey), a National Institutes of Health Clinical Research Center grant to Indiana University (M01-RR00750), and a Department of Housing and Urban Development grant (B-01-SP-IN-0200).

Given the efficacy and safety profiles of atypical antipsychotics, their potential to cause weight gain represents not a barrier to access but a side effect to be managed. Behavioral and/or drug interventions can help protect patients from the medical risks and social consequences of weight gain during antipsychotic treatment.

Let’s look at possible mechanisms of antipsychotic-induced weight gain and a rational strategy for controlling weight in patients taking these medications. This strategy applies to all atypical antipsychotics and psychiatric diagnoses.

Mechanisms of weight gain

Neuroleptic antipsychotics may act on the hypothalamic feeding center and directly stimulate appetite, a dynamic that was suggested 20 years ago.¹ More recent evidence suggests that antagonism of serotonin (5-HT2C) or histamine (H1) receptors may play a role in antipsychotic-related weight gain. Other neurotransmitters and receptors may also be involved.

Serotonin receptor antagonism. Agents that stimulate 5-HT2C receptors—such as fenfluramine and M-chlorophenylpiperazine² —have been associated with weight loss. Conversely, agents that antagonize these receptors have been hypothesized to increase appetite and cause weight gain.³

For example, a strain of mice craved carbohydrates and became obese after the genes for 5-HT2C receptors were removed.⁴ Atypical antipsychotics also antagonize 5-HT2C receptors more than the older neuroleptics do, which may explain the atypicals’ greater associated risk for weight gain.

Histamine receptor antagonism. Other researchers have suggested that antipsychotic-induced weight gain is associated less with serotonin receptors than with histamine receptor antagonism:

• Astemizole—a potent H1 receptor antagonist used to treat allergic rhinitis—was the first medication associated with weight gain by this mechanism.⁵
• Wirshing et al⁶ recently reported an exponential relationship between antipsychotics’ H1 receptor affinities and maximum weight gain.

Clozapine and olanzapine have very strong binding affinity to both 5-HT2C and H1 receptors. This characteristic may explain why patients often experience increased appetite and weight gain while taking these antipsychotics.

Other neurotransmitters. Atypical antipsychotics have diverse pharmacologic profiles, and their interactions with dopamine and other neurotransmitter receptors produce a variety of effects (Table 1). These neurotransmitter systems and receptor subtypes appear to help regulate food intake and energy homeostasis and may play a role in weight gain associated with antipsychotic use.⁷ For example:

• Clozapine and olanzapine have a higher affinity for serotonin receptor subtypes 5-HT2A and 5-HT2C and for H1 and muscarinic (M1) receptors than they do for D2 receptors. This preferential antagonism of 5-HT2A versus D2 receptors is a defining characteristic of novel antipsychotics and explains why they offer broader efficacy and fewer side effects than the older neuroleptics. However, 5-HT2C receptor antagonism has been implicated as a cause of increased appetite.⁴
• Clozapine, but not olanzapine, also has a higher affinity for adrenergic (1) receptors than for D2 receptors. Clozapine is associated with greater mean weight gain than olanzapine, risperidone, or ziprasidone.⁸
• Risperidone—with a lower weight gain potential than most atypicals—displays high affinity for 5-HT2A and 1 receptors and a lower affinity for 5-HT2C receptors than for D2 receptors.⁸
• Ziprasidone’s weight gain potential is even less than risperidone’s, and the exact mechanism is unknown.⁸ Some animal studies suggest that ziprasidone’s effects on the noradrenergic system may explain its low weight gain potential.⁹
• Aripiprazole’s long-term weight gain potential is not yet known.

Table 1

RECEPTOR BINDING AFFINITIES OF ATYPICAL ANTIPSYCHOTICS

Drug	Dopamine	Serotonin		∂1 adrenergic	Histamine	Muscarinic
	D2	5HT2A	5HT2C		H1	M1
Clozapine	+	++++	+++	+++	++
Olanzapine	++	++++	++++	−	++	−
Quetiapine	+	+	+	+++	++	−
Risperidone	++++	+++++	++	+	+++	−
Ziprasidone	++++	+++++	+	0	++	−

A strategy for managing weight gain

Four predictors of weight gain have been identified in patients with schizophrenia:

• better clinical outcome
• low baseline body mass index
• younger age
• increase in appetite during treatment.¹⁰

When appetite increases, patients are at risk of overeating to satisfy their hunger. An average increase of 500 calories per day will cause an average weight gain of 1 lb per week. Therefore, minimizing an increase in caloric intake may minimize weight gain.

One can lose weight by reducing caloric intake or increasing caloric output, such as with exercise. Thus, behavioral interventions focusing on both nutritional education and exercise are showing benefit in minimizing antipsychotic-related weight gain. The “wellness clinic” described by Wirshing et al achieved weight loss in patients taking antipsychotics through rigorous interventions, including education, exercise classes, and group support.⁶

A rational approach for minimizing weight gain in patients taking antipsychotics is summarized in Table 2. This strategy combines nutritional and exercise education and drug therapy, when indicated.

Effect of behavioral interventions

Many patients who have followed behavioral interventions that emphasize nutrition and exercise have lost at least some of the weight they gained during antipsychotic treatment:

• In a study by O’Keefe, nearly 80% of patients who gained >20 lbs while taking antipsychotics then lost at least 10 lbs while in behavioral intervention programs.¹¹
• Patients with schizophrenia or schizoaffective disorder who experienced olanzapine-related weight gain lost weight while attending a 10-week Weight Watchers program.¹²
• Patients who gained weight while taking antipsychotics lost weight with a step-wise behavioral approach that included increasingly intensive interventions (self-weighing, food diaries, nutrition consultation, and attendance at a “wellness clinic”).⁶
• 70% of 74 psychiatric inpatients lost weight across 6 to 34 months with a reduced-calorie diet, group therapy, and behavior modification.¹³

 

The effectiveness of weight management programs associated with antipsychotics may depend on the target population. In a retrospective chart review, Cohen et al found that calorie restriction did not lead to weight loss among 50 adult inpatients with mental retardation who were being treated with risperidone.¹⁴

Timing is important. During olanzapine treatment, mean weight gain has been reported to plateau after approximately 39 weeks, with the most rapid gains in the first 12 weeks.⁶ Thus, early weight control efforts likely would be most effective. Two small, prospective studies suggest that starting behavioral interventions before you start olanzapine therapy may be the most effective strategy to minimize weight gain.

In the first study—a randomized trial of 12 patients with schizophrenia—those who received an educational intervention prior to starting olanzapine treatment gained a mean 1 lb in 4 weeks, compared with 6.4 lbs in a standard-care group.¹⁵ The behavioral intervention included a weekly 1-hour class using educational materials on nutrition and exercise.

In the second study, our group offered 22 psychiatric outpatients a nutrition course before starting olanzapine treatment.¹⁶ We included 17 patients with psychotic disorders and 5 with nonpsychotic diagnoses—including major depressive disorder, bipolar disorder, and stuttering—to compare antipsychotic-related weight gain between psychotic and nonpsychotic populations.

We began by talking with each patient for 5 minutes about the following nutritional concepts:

• Weight gain is associated with increased appetite.
• The more you eat, the more weight you gain.
• To reduce hunger, it is better to snack on fruits, carrots, broccoli, or low-fat crackers than on high-calorie “junk food” such as potato chips, ice cream, candy, and cake.
• Drink water or diet sodas instead of sugary soft drinks.

At follow-up visits, we spent 2 minutes reinforcing the educational messages by:

• asking if patients’ appetite had increased
• re-emphasizing that they should eat low-fat snacks to reduce hunger and drink water or diet sodas instead of sugary soft drinks.

After about 7 months, the mean weight gain from olanzapine therapy was 5.27 lbs, which is 40 to 60% less than that seen in studies of olanzapine without structured interventions.^6,8,17 Mean weight gain was 5 lbs for the psychotic patients and 6.2 lbs for the nonpsychotic group, which suggested that patients with schizophrenia or schizoaffective disorders may benefit from nutritional education.

Table 2

STRATEGY FOR MANAGING WEIGHT IN PATIENTS TAKING ANTIPSYCHOTICS

Begin nutritional and exercise education before starting antipsychotic treatment. Monitor weight weekly in the first 4 to 6 weeks of antipsychotic therapy, when the risk for weight gain is highest. Ask if the patient’s appetite has increased. If a patient gains >10 lbs during the first 4 to 6 weeks, consider adding nizatidine, 300 mg bid; topiramate, 100 to 200 mg/d; or amantadine, 100 mg bid, to the antipsychotic regimen. Continue adjunctive therapy until appetite has decreased and weight gain has stabilized, then taper off the medication and continue to monitor weight. Emphasize the importance of proper food choices. Review the patient’s diet at every visit. Provide very specific nutritional education. Discourage eating “junk food” such as chocolate, potato chips, cake, cookies, and soft drinks, and encourage drinking water and eating fruits and vegetables.

Medications for weight control

Three medications—nizatidine, topiramate, and amantadine—have shown some effect in controlling weight gain when taken concomitantly with atypical antipsychotics. These medications affect different receptors, and how they affect weight gain is not entirely understood.

Nizatidine—a selective histamine (H2) receptor antagonist—was shown to be significantly more effective than placebo in reducing olanzapine-related weight gain when given to 132 patients at 300 mg bid.¹⁸

Topiramate is believed to stimulate 5-HT2C receptors, thus suppressing the increased appetite caused by 5-HT2C antagonism. Among 13 bipolar patients with significant weight gain associated with olanzapine treatment, 73% lost weight with topiramate at 90.4 +/- 48.4 mg/d.¹⁸

Amantadine has also been shown to minimize weight gain without worsening psychotic symptoms. A case series reported a weight gain of 15.8 lbs in patients taking olanzapine alone, compared with 7.7 lbs in patients taking olanzapine plus amantadine.¹⁹

Related resources

• Wirshing DA, Wirshing WC, Ksyar L, et al. Novel antipsychotics: a comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-63.
• Casey DE, Zorn S. The pharmacology of weight gain with antipsychotics. J Clin Psychiatry 2001;62 (suppl 7):4-10.

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Nizatidine • Axid
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Ziprasidone • Geodon

Disclosure

Dr. Nguyen is a speaker for Eli Lilly and Co. and GlaxoSmithKline; receives research support from Eli Lilly and Co., GlaxoSmithKline, and Forest Laboratories; and is a consultant to Eli Lilly and Co., Organon, and GlaxoSmithKline.

 

Dr. Yu is a speaker for Cephalon Inc., Eli Lilly and Co., Novartis Pharmaceuticals Corp., and Pfizer Inc.; receives research/grant support from Cephalon, Inc. and Eli Lilly and Co.; and is a consultant to Eli Lilly and Co.

Dr. Maguire receives research support from, is a consultant to, and/or is a speaker for Eli Lilly and Co., Pfizer Inc., Forest Laboratories, and GlaxoSmithKline.

Acknowledgment

The authors wish to thank David Franklin, MS, neuroscientist; Chris Gordon, MD, resident; and Sam Truong, senior undergraduate student, University of California, Irvine, as well as Leanne Stoneking, MS, fourth-year medical student, Creighton University Medical School, for their assistance in preparing this manuscript.

Given the efficacy and safety profiles of atypical antipsychotics, their potential to cause weight gain represents not a barrier to access but a side effect to be managed. Behavioral and/or drug interventions can help protect patients from the medical risks and social consequences of weight gain during antipsychotic treatment.

Let’s look at possible mechanisms of antipsychotic-induced weight gain and a rational strategy for controlling weight in patients taking these medications. This strategy applies to all atypical antipsychotics and psychiatric diagnoses.

Mechanisms of weight gain

Neuroleptic antipsychotics may act on the hypothalamic feeding center and directly stimulate appetite, a dynamic that was suggested 20 years ago.¹ More recent evidence suggests that antagonism of serotonin (5-HT2C) or histamine (H1) receptors may play a role in antipsychotic-related weight gain. Other neurotransmitters and receptors may also be involved.

Serotonin receptor antagonism. Agents that stimulate 5-HT2C receptors—such as fenfluramine and M-chlorophenylpiperazine² —have been associated with weight loss. Conversely, agents that antagonize these receptors have been hypothesized to increase appetite and cause weight gain.³

For example, a strain of mice craved carbohydrates and became obese after the genes for 5-HT2C receptors were removed.⁴ Atypical antipsychotics also antagonize 5-HT2C receptors more than the older neuroleptics do, which may explain the atypicals’ greater associated risk for weight gain.

Histamine receptor antagonism. Other researchers have suggested that antipsychotic-induced weight gain is associated less with serotonin receptors than with histamine receptor antagonism:

• Astemizole—a potent H1 receptor antagonist used to treat allergic rhinitis—was the first medication associated with weight gain by this mechanism.⁵
• Wirshing et al⁶ recently reported an exponential relationship between antipsychotics’ H1 receptor affinities and maximum weight gain.

Clozapine and olanzapine have very strong binding affinity to both 5-HT2C and H1 receptors. This characteristic may explain why patients often experience increased appetite and weight gain while taking these antipsychotics.

Other neurotransmitters. Atypical antipsychotics have diverse pharmacologic profiles, and their interactions with dopamine and other neurotransmitter receptors produce a variety of effects (Table 1). These neurotransmitter systems and receptor subtypes appear to help regulate food intake and energy homeostasis and may play a role in weight gain associated with antipsychotic use.⁷ For example:

• Clozapine and olanzapine have a higher affinity for serotonin receptor subtypes 5-HT2A and 5-HT2C and for H1 and muscarinic (M1) receptors than they do for D2 receptors. This preferential antagonism of 5-HT2A versus D2 receptors is a defining characteristic of novel antipsychotics and explains why they offer broader efficacy and fewer side effects than the older neuroleptics. However, 5-HT2C receptor antagonism has been implicated as a cause of increased appetite.⁴
• Clozapine, but not olanzapine, also has a higher affinity for adrenergic (1) receptors than for D2 receptors. Clozapine is associated with greater mean weight gain than olanzapine, risperidone, or ziprasidone.⁸
• Risperidone—with a lower weight gain potential than most atypicals—displays high affinity for 5-HT2A and 1 receptors and a lower affinity for 5-HT2C receptors than for D2 receptors.⁸
• Ziprasidone’s weight gain potential is even less than risperidone’s, and the exact mechanism is unknown.⁸ Some animal studies suggest that ziprasidone’s effects on the noradrenergic system may explain its low weight gain potential.⁹
• Aripiprazole’s long-term weight gain potential is not yet known.

Table 1

RECEPTOR BINDING AFFINITIES OF ATYPICAL ANTIPSYCHOTICS

Drug	Dopamine	Serotonin		∂1 adrenergic	Histamine	Muscarinic
	D2	5HT2A	5HT2C		H1	M1
Clozapine	+	++++	+++	+++	++
Olanzapine	++	++++	++++	−	++	−
Quetiapine	+	+	+	+++	++	−
Risperidone	++++	+++++	++	+	+++	−
Ziprasidone	++++	+++++	+	0	++	−

A strategy for managing weight gain

Four predictors of weight gain have been identified in patients with schizophrenia:

• better clinical outcome
• low baseline body mass index
• younger age
• increase in appetite during treatment.¹⁰

When appetite increases, patients are at risk of overeating to satisfy their hunger. An average increase of 500 calories per day will cause an average weight gain of 1 lb per week. Therefore, minimizing an increase in caloric intake may minimize weight gain.

One can lose weight by reducing caloric intake or increasing caloric output, such as with exercise. Thus, behavioral interventions focusing on both nutritional education and exercise are showing benefit in minimizing antipsychotic-related weight gain. The “wellness clinic” described by Wirshing et al achieved weight loss in patients taking antipsychotics through rigorous interventions, including education, exercise classes, and group support.⁶

A rational approach for minimizing weight gain in patients taking antipsychotics is summarized in Table 2. This strategy combines nutritional and exercise education and drug therapy, when indicated.

Effect of behavioral interventions

Many patients who have followed behavioral interventions that emphasize nutrition and exercise have lost at least some of the weight they gained during antipsychotic treatment:

• In a study by O’Keefe, nearly 80% of patients who gained >20 lbs while taking antipsychotics then lost at least 10 lbs while in behavioral intervention programs.¹¹
• Patients with schizophrenia or schizoaffective disorder who experienced olanzapine-related weight gain lost weight while attending a 10-week Weight Watchers program.¹²
• Patients who gained weight while taking antipsychotics lost weight with a step-wise behavioral approach that included increasingly intensive interventions (self-weighing, food diaries, nutrition consultation, and attendance at a “wellness clinic”).⁶
• 70% of 74 psychiatric inpatients lost weight across 6 to 34 months with a reduced-calorie diet, group therapy, and behavior modification.¹³

 

The effectiveness of weight management programs associated with antipsychotics may depend on the target population. In a retrospective chart review, Cohen et al found that calorie restriction did not lead to weight loss among 50 adult inpatients with mental retardation who were being treated with risperidone.¹⁴

Timing is important. During olanzapine treatment, mean weight gain has been reported to plateau after approximately 39 weeks, with the most rapid gains in the first 12 weeks.⁶ Thus, early weight control efforts likely would be most effective. Two small, prospective studies suggest that starting behavioral interventions before you start olanzapine therapy may be the most effective strategy to minimize weight gain.

In the first study—a randomized trial of 12 patients with schizophrenia—those who received an educational intervention prior to starting olanzapine treatment gained a mean 1 lb in 4 weeks, compared with 6.4 lbs in a standard-care group.¹⁵ The behavioral intervention included a weekly 1-hour class using educational materials on nutrition and exercise.

In the second study, our group offered 22 psychiatric outpatients a nutrition course before starting olanzapine treatment.¹⁶ We included 17 patients with psychotic disorders and 5 with nonpsychotic diagnoses—including major depressive disorder, bipolar disorder, and stuttering—to compare antipsychotic-related weight gain between psychotic and nonpsychotic populations.

We began by talking with each patient for 5 minutes about the following nutritional concepts:

• Weight gain is associated with increased appetite.
• The more you eat, the more weight you gain.
• To reduce hunger, it is better to snack on fruits, carrots, broccoli, or low-fat crackers than on high-calorie “junk food” such as potato chips, ice cream, candy, and cake.
• Drink water or diet sodas instead of sugary soft drinks.

At follow-up visits, we spent 2 minutes reinforcing the educational messages by:

• asking if patients’ appetite had increased
• re-emphasizing that they should eat low-fat snacks to reduce hunger and drink water or diet sodas instead of sugary soft drinks.

After about 7 months, the mean weight gain from olanzapine therapy was 5.27 lbs, which is 40 to 60% less than that seen in studies of olanzapine without structured interventions.^6,8,17 Mean weight gain was 5 lbs for the psychotic patients and 6.2 lbs for the nonpsychotic group, which suggested that patients with schizophrenia or schizoaffective disorders may benefit from nutritional education.

Table 2

STRATEGY FOR MANAGING WEIGHT IN PATIENTS TAKING ANTIPSYCHOTICS

Begin nutritional and exercise education before starting antipsychotic treatment. Monitor weight weekly in the first 4 to 6 weeks of antipsychotic therapy, when the risk for weight gain is highest. Ask if the patient’s appetite has increased. If a patient gains >10 lbs during the first 4 to 6 weeks, consider adding nizatidine, 300 mg bid; topiramate, 100 to 200 mg/d; or amantadine, 100 mg bid, to the antipsychotic regimen. Continue adjunctive therapy until appetite has decreased and weight gain has stabilized, then taper off the medication and continue to monitor weight. Emphasize the importance of proper food choices. Review the patient’s diet at every visit. Provide very specific nutritional education. Discourage eating “junk food” such as chocolate, potato chips, cake, cookies, and soft drinks, and encourage drinking water and eating fruits and vegetables.

Medications for weight control

Three medications—nizatidine, topiramate, and amantadine—have shown some effect in controlling weight gain when taken concomitantly with atypical antipsychotics. These medications affect different receptors, and how they affect weight gain is not entirely understood.

Nizatidine—a selective histamine (H2) receptor antagonist—was shown to be significantly more effective than placebo in reducing olanzapine-related weight gain when given to 132 patients at 300 mg bid.¹⁸

Topiramate is believed to stimulate 5-HT2C receptors, thus suppressing the increased appetite caused by 5-HT2C antagonism. Among 13 bipolar patients with significant weight gain associated with olanzapine treatment, 73% lost weight with topiramate at 90.4 +/- 48.4 mg/d.¹⁸

Amantadine has also been shown to minimize weight gain without worsening psychotic symptoms. A case series reported a weight gain of 15.8 lbs in patients taking olanzapine alone, compared with 7.7 lbs in patients taking olanzapine plus amantadine.¹⁹

Related resources

• Wirshing DA, Wirshing WC, Ksyar L, et al. Novel antipsychotics: a comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-63.
• Casey DE, Zorn S. The pharmacology of weight gain with antipsychotics. J Clin Psychiatry 2001;62 (suppl 7):4-10.

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Nizatidine • Axid
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Ziprasidone • Geodon

Disclosure

Dr. Nguyen is a speaker for Eli Lilly and Co. and GlaxoSmithKline; receives research support from Eli Lilly and Co., GlaxoSmithKline, and Forest Laboratories; and is a consultant to Eli Lilly and Co., Organon, and GlaxoSmithKline.

 

Dr. Yu is a speaker for Cephalon Inc., Eli Lilly and Co., Novartis Pharmaceuticals Corp., and Pfizer Inc.; receives research/grant support from Cephalon, Inc. and Eli Lilly and Co.; and is a consultant to Eli Lilly and Co.

Dr. Maguire receives research support from, is a consultant to, and/or is a speaker for Eli Lilly and Co., Pfizer Inc., Forest Laboratories, and GlaxoSmithKline.

Acknowledgment

The authors wish to thank David Franklin, MS, neuroscientist; Chris Gordon, MD, resident; and Sam Truong, senior undergraduate student, University of California, Irvine, as well as Leanne Stoneking, MS, fourth-year medical student, Creighton University Medical School, for their assistance in preparing this manuscript.

Given the efficacy and safety profiles of atypical antipsychotics, their potential to cause weight gain represents not a barrier to access but a side effect to be managed. Behavioral and/or drug interventions can help protect patients from the medical risks and social consequences of weight gain during antipsychotic treatment.

Let’s look at possible mechanisms of antipsychotic-induced weight gain and a rational strategy for controlling weight in patients taking these medications. This strategy applies to all atypical antipsychotics and psychiatric diagnoses.

Mechanisms of weight gain

Neuroleptic antipsychotics may act on the hypothalamic feeding center and directly stimulate appetite, a dynamic that was suggested 20 years ago.¹ More recent evidence suggests that antagonism of serotonin (5-HT2C) or histamine (H1) receptors may play a role in antipsychotic-related weight gain. Other neurotransmitters and receptors may also be involved.

Serotonin receptor antagonism. Agents that stimulate 5-HT2C receptors—such as fenfluramine and M-chlorophenylpiperazine² —have been associated with weight loss. Conversely, agents that antagonize these receptors have been hypothesized to increase appetite and cause weight gain.³

For example, a strain of mice craved carbohydrates and became obese after the genes for 5-HT2C receptors were removed.⁴ Atypical antipsychotics also antagonize 5-HT2C receptors more than the older neuroleptics do, which may explain the atypicals’ greater associated risk for weight gain.

Histamine receptor antagonism. Other researchers have suggested that antipsychotic-induced weight gain is associated less with serotonin receptors than with histamine receptor antagonism:

• Astemizole—a potent H1 receptor antagonist used to treat allergic rhinitis—was the first medication associated with weight gain by this mechanism.⁵
• Wirshing et al⁶ recently reported an exponential relationship between antipsychotics’ H1 receptor affinities and maximum weight gain.

Clozapine and olanzapine have very strong binding affinity to both 5-HT2C and H1 receptors. This characteristic may explain why patients often experience increased appetite and weight gain while taking these antipsychotics.

Other neurotransmitters. Atypical antipsychotics have diverse pharmacologic profiles, and their interactions with dopamine and other neurotransmitter receptors produce a variety of effects (Table 1). These neurotransmitter systems and receptor subtypes appear to help regulate food intake and energy homeostasis and may play a role in weight gain associated with antipsychotic use.⁷ For example:

• Clozapine and olanzapine have a higher affinity for serotonin receptor subtypes 5-HT2A and 5-HT2C and for H1 and muscarinic (M1) receptors than they do for D2 receptors. This preferential antagonism of 5-HT2A versus D2 receptors is a defining characteristic of novel antipsychotics and explains why they offer broader efficacy and fewer side effects than the older neuroleptics. However, 5-HT2C receptor antagonism has been implicated as a cause of increased appetite.⁴
• Clozapine, but not olanzapine, also has a higher affinity for adrenergic (1) receptors than for D2 receptors. Clozapine is associated with greater mean weight gain than olanzapine, risperidone, or ziprasidone.⁸
• Risperidone—with a lower weight gain potential than most atypicals—displays high affinity for 5-HT2A and 1 receptors and a lower affinity for 5-HT2C receptors than for D2 receptors.⁸
• Ziprasidone’s weight gain potential is even less than risperidone’s, and the exact mechanism is unknown.⁸ Some animal studies suggest that ziprasidone’s effects on the noradrenergic system may explain its low weight gain potential.⁹
• Aripiprazole’s long-term weight gain potential is not yet known.

Table 1

RECEPTOR BINDING AFFINITIES OF ATYPICAL ANTIPSYCHOTICS

Drug	Dopamine	Serotonin		∂1 adrenergic	Histamine	Muscarinic
	D2	5HT2A	5HT2C		H1	M1
Clozapine	+	++++	+++	+++	++
Olanzapine	++	++++	++++	−	++	−
Quetiapine	+	+	+	+++	++	−
Risperidone	++++	+++++	++	+	+++	−
Ziprasidone	++++	+++++	+	0	++	−

A strategy for managing weight gain

Four predictors of weight gain have been identified in patients with schizophrenia:

• better clinical outcome
• low baseline body mass index
• younger age
• increase in appetite during treatment.¹⁰

When appetite increases, patients are at risk of overeating to satisfy their hunger. An average increase of 500 calories per day will cause an average weight gain of 1 lb per week. Therefore, minimizing an increase in caloric intake may minimize weight gain.

One can lose weight by reducing caloric intake or increasing caloric output, such as with exercise. Thus, behavioral interventions focusing on both nutritional education and exercise are showing benefit in minimizing antipsychotic-related weight gain. The “wellness clinic” described by Wirshing et al achieved weight loss in patients taking antipsychotics through rigorous interventions, including education, exercise classes, and group support.⁶

A rational approach for minimizing weight gain in patients taking antipsychotics is summarized in Table 2. This strategy combines nutritional and exercise education and drug therapy, when indicated.

Effect of behavioral interventions

Many patients who have followed behavioral interventions that emphasize nutrition and exercise have lost at least some of the weight they gained during antipsychotic treatment:

• In a study by O’Keefe, nearly 80% of patients who gained >20 lbs while taking antipsychotics then lost at least 10 lbs while in behavioral intervention programs.¹¹
• Patients with schizophrenia or schizoaffective disorder who experienced olanzapine-related weight gain lost weight while attending a 10-week Weight Watchers program.¹²
• Patients who gained weight while taking antipsychotics lost weight with a step-wise behavioral approach that included increasingly intensive interventions (self-weighing, food diaries, nutrition consultation, and attendance at a “wellness clinic”).⁶
• 70% of 74 psychiatric inpatients lost weight across 6 to 34 months with a reduced-calorie diet, group therapy, and behavior modification.¹³

 

The effectiveness of weight management programs associated with antipsychotics may depend on the target population. In a retrospective chart review, Cohen et al found that calorie restriction did not lead to weight loss among 50 adult inpatients with mental retardation who were being treated with risperidone.¹⁴

Timing is important. During olanzapine treatment, mean weight gain has been reported to plateau after approximately 39 weeks, with the most rapid gains in the first 12 weeks.⁶ Thus, early weight control efforts likely would be most effective. Two small, prospective studies suggest that starting behavioral interventions before you start olanzapine therapy may be the most effective strategy to minimize weight gain.

In the first study—a randomized trial of 12 patients with schizophrenia—those who received an educational intervention prior to starting olanzapine treatment gained a mean 1 lb in 4 weeks, compared with 6.4 lbs in a standard-care group.¹⁵ The behavioral intervention included a weekly 1-hour class using educational materials on nutrition and exercise.

In the second study, our group offered 22 psychiatric outpatients a nutrition course before starting olanzapine treatment.¹⁶ We included 17 patients with psychotic disorders and 5 with nonpsychotic diagnoses—including major depressive disorder, bipolar disorder, and stuttering—to compare antipsychotic-related weight gain between psychotic and nonpsychotic populations.

We began by talking with each patient for 5 minutes about the following nutritional concepts:

• Weight gain is associated with increased appetite.
• The more you eat, the more weight you gain.
• To reduce hunger, it is better to snack on fruits, carrots, broccoli, or low-fat crackers than on high-calorie “junk food” such as potato chips, ice cream, candy, and cake.
• Drink water or diet sodas instead of sugary soft drinks.

At follow-up visits, we spent 2 minutes reinforcing the educational messages by:

• asking if patients’ appetite had increased
• re-emphasizing that they should eat low-fat snacks to reduce hunger and drink water or diet sodas instead of sugary soft drinks.

After about 7 months, the mean weight gain from olanzapine therapy was 5.27 lbs, which is 40 to 60% less than that seen in studies of olanzapine without structured interventions.^6,8,17 Mean weight gain was 5 lbs for the psychotic patients and 6.2 lbs for the nonpsychotic group, which suggested that patients with schizophrenia or schizoaffective disorders may benefit from nutritional education.

Table 2

STRATEGY FOR MANAGING WEIGHT IN PATIENTS TAKING ANTIPSYCHOTICS

Begin nutritional and exercise education before starting antipsychotic treatment. Monitor weight weekly in the first 4 to 6 weeks of antipsychotic therapy, when the risk for weight gain is highest. Ask if the patient’s appetite has increased. If a patient gains >10 lbs during the first 4 to 6 weeks, consider adding nizatidine, 300 mg bid; topiramate, 100 to 200 mg/d; or amantadine, 100 mg bid, to the antipsychotic regimen. Continue adjunctive therapy until appetite has decreased and weight gain has stabilized, then taper off the medication and continue to monitor weight. Emphasize the importance of proper food choices. Review the patient’s diet at every visit. Provide very specific nutritional education. Discourage eating “junk food” such as chocolate, potato chips, cake, cookies, and soft drinks, and encourage drinking water and eating fruits and vegetables.

Medications for weight control

Three medications—nizatidine, topiramate, and amantadine—have shown some effect in controlling weight gain when taken concomitantly with atypical antipsychotics. These medications affect different receptors, and how they affect weight gain is not entirely understood.

Nizatidine—a selective histamine (H2) receptor antagonist—was shown to be significantly more effective than placebo in reducing olanzapine-related weight gain when given to 132 patients at 300 mg bid.¹⁸

Topiramate is believed to stimulate 5-HT2C receptors, thus suppressing the increased appetite caused by 5-HT2C antagonism. Among 13 bipolar patients with significant weight gain associated with olanzapine treatment, 73% lost weight with topiramate at 90.4 +/- 48.4 mg/d.¹⁸

Amantadine has also been shown to minimize weight gain without worsening psychotic symptoms. A case series reported a weight gain of 15.8 lbs in patients taking olanzapine alone, compared with 7.7 lbs in patients taking olanzapine plus amantadine.¹⁹

Related resources

• Wirshing DA, Wirshing WC, Ksyar L, et al. Novel antipsychotics: a comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-63.
• Casey DE, Zorn S. The pharmacology of weight gain with antipsychotics. J Clin Psychiatry 2001;62 (suppl 7):4-10.

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Nizatidine • Axid
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Topiramate • Topamax
• Ziprasidone • Geodon

Disclosure

Dr. Nguyen is a speaker for Eli Lilly and Co. and GlaxoSmithKline; receives research support from Eli Lilly and Co., GlaxoSmithKline, and Forest Laboratories; and is a consultant to Eli Lilly and Co., Organon, and GlaxoSmithKline.

 

Dr. Yu is a speaker for Cephalon Inc., Eli Lilly and Co., Novartis Pharmaceuticals Corp., and Pfizer Inc.; receives research/grant support from Cephalon, Inc. and Eli Lilly and Co.; and is a consultant to Eli Lilly and Co.

Dr. Maguire receives research support from, is a consultant to, and/or is a speaker for Eli Lilly and Co., Pfizer Inc., Forest Laboratories, and GlaxoSmithKline.

Acknowledgment

The authors wish to thank David Franklin, MS, neuroscientist; Chris Gordon, MD, resident; and Sam Truong, senior undergraduate student, University of California, Irvine, as well as Leanne Stoneking, MS, fourth-year medical student, Creighton University Medical School, for their assistance in preparing this manuscript.